Triple Combination Release Multi-Layered Tablet

ABSTRACT

This invention pertains to a multi-layered tablet for a triple combination release of active agents to an environment of use. More particularly, the invention pertains to a multi-layered tablet ( 1 ) comprising two external drug-containing layers ( 2  and  3 ) in stacked arrangement with respect to and on opposite sides of an oral dosage form ( 4 ) that provides a triple combination release of at least one active agent. In one embodiment of the invention the dosage form is an osmotic device. In another embodiment of the invention the dosage form is a gastro-resistant coated core. In yet another embodiment of the invention the dosage form is a matrix tablet. In a different embodiment the dosage form is a hard capsule.

CROSS-REFERENCE TO EARLIER FILED APPLICATIONS

This application is a continuation of PCT International Application No.PCT/CR2006/00008 filed Dec. 20, 2006, which claims the benefit of U.S.Provisional Application No. 60/754,972 filed Dec. 29, 2005, the entiredisclosures of which are hereby incorporated by reference.

FIELD OF THE INVENTION

This invention pertains to a multi-layered tablet for a triplecombination release of active agents to an environment of use. Moreparticularly, the invention pertains to a multi-layered tabletcomprising two external drug-containing layers in stacked arrangementwith respect to and on opposite sides of an oral dosage form thatprovides a triple combination release of at least one active agent.

BACKGROUND OF THE INVENTION

Multi-layered tablets that provide different release profiles for one ormore different drugs are known.

U.S. Pat. No. 4,999,226 to Schock et al. discloses a multi-layeredtablet having two different drug-containing layers separated by a layercomprising a pharmaceutically inert excipient. The inert layer providesa barrier layer between the drugs layers, in order to solve the problemsassociated with the physical and chemical incompatibilities between thedrugs.

U.S. Pat. No. 5,342,627 to Glaxo Canada Inc. discloses a device for therelease of at least one active substance into a fluid medium bydissolution comprising a covering, which is impermeable to the activesubstance and the fluid, or is swellable or slowly soluble in saidfluid, having at least one aperture therein and defining a shapedcavity, the cavity being filled by a shaped core comprising the activesubstance. The covering composition is compressed onto a pre-shaped coreof active substance. The geometric configuration of thecompression-coated core controls the release profile of drugs. Thedevice may be provided with an outer soluble coating which provides aninitial delay before release of active substance begins, oralternatively provides an immediate dose of active substance.

The U.S. Pregrant Patent Application Publication No. 20020128251 toGlaxoSmithKline discloses a layered tablet formulation comprising animmediate release layer and a slow release layer. The layered tablet mayhave two layers, or two layers plus one or more barrier layer, as wellas a coating layer. The coating layer may itself contain active materialcontent, and may, for example, be an immediate release layer, whichimmediately disintegrates in contact with water or aqueous media torelease its active material content.

U.S. Pregrant Patent Application Publication No. 20040115265 to BristolMeyers Squibb discloses a multi-layered tablet that includes twodrug-containing layers separated by a middle barrier layer to minimizeinteraction of the drugs.

U.S. Pat. No. 6,660,299 to Beecham Pharmaceuticals Limited discloses amulti-layered tablet consisting of a slow release layer, a rapid releaselayer and optionally a barrier layer, which may be located between therespective first and second layers, and/or on one or more of the outersurfaces of the first and second layers, for example the end faces ofthe layers of a substantially cylindrical tablet. The tablet consistingof an immediate release and a slow release layer can be optionallycoated with a coating layer. The barrier layer is designed to retainsufficient physical integrity at least until complete or substantiallycomplete release of drug.

SCOLR Pharma, Inc. (Bellevue, Wash.) has filed an application with theUnited States Patent Office on an Asymmetrical Multiple Layered Tabletfor Controlled Release. The technology is reportedly designed to workwith single or multiple ingredients and/or drugs, allowing thoseingredients/drugs to be programmed for release at pre-selected ratesand/or at pre-selected regions within the body.

SkyPharma offers the GEOMATRIX™ combination tablet, which is a bimodalrelease multi-layered tablet made by compression. The GEOMATRIX™ tabletcomprises two opposing barrier layers that module release of drug from amiddle layer to provide controlled release of drug from the middle layer(Conte et al., Pharm. Technol. 22, No. 3, 174-82, 1998). This technologyis further described in U.S. Pat. No. 4,839,177 to Jagotec AG.

U.S. Pat. No. 5,738,874, U.S. Pat. No. 6,183,778, and U.S. Pat. No.6,294,200 to Jagotec AG disclose multi-layered tablet formulations.

The SMARTRIX™ combination tablet (www.smartrix.com) is a bimodal releasemulti-layered tablet having a controlled release drug-containing layer,containing a first drug, placed between two stacked rapidly erodinglayers, either one or both of which contains a different second drug.The middle layer has a biconcave surface whereas the upper and lowerlayers have a convex layer that mates with the middle layer and an outerflat surface. The shape of the surface(s) between the layers can bevaried to provide specific drug release profiles from the core.

PCT International Publication No. WO 03/105809 discloses a two-layeredtablet containing pioglitazone in immediate release form and metforminin prolonged release form.

PCT International Publication No. WO 03/101431, U.S. Pregrant PatentApplication Publication No. 20030092724, and U.S. Pat. No. 6,372,255disclose a bi-layered tablet having an immediate release layer and acontrolled release layer.

Japanese Patent Application No. 1989-287048, French Patent ApplicationNo. 1999-0000625, U.S. Pat. No. 5,637,320, and Omori at al. (Pharm.Tech. Jpn, 2001, 17(9), pp. 1429-1432, 1435-1441) disclose layeredformulations that provide an immediate and slow release of drug.

European Patent Application EP 1260216 discloses a concentricallybi-layered tablet comprising a first portion having at least onediscrete outer layer comprising a therapeutically effective amount of atleast one pharmaceutically active ingredient capable of intraoraladministration, and a second portion located within said first portionthat comprises a therapeutically effective amount of at least onepharmaceutically active ingredient capable of oral administration andwhich is releasable and orally ingestible by the patient after the outerlayer has disintegrated or has dissolved intraorally. The second portioncan provide immediate release or sustained release of thepharmaceutically active ingredient.

Japanese Patent Application No. 1996-211279 discloses a multi-layeredtablet having a variety of different layers.

U.S. Pregrant Patent Application Publications No. 20040253311 and No.20040186184 disclose a multi-layered tablet having a combination of adecongestant and an anti-histamine.

PCT International Publication No. WO 04/064815 discloses a three-layeredtablet having an immediate release layer of famotidine, an immediaterelease layer of aspirin and a slow release layer of famotidine.

U.S. Pat. No. 5,093,200 discloses a multi-layered tablet having a rapidrelease layer, a slow release layer and metal stearate layer between theother two layers.

U.S. Pat. No. 5,681,583 discloses a multi-layered tablet having avariety of different layers for rapid, controlled and gradual release.

U.S. Pat. No. 5,395,626 and U.S. Pat. No. 5,474,786 disclosesmulti-layered particles that comprise concentric coatings to provideimmediate and sustained release of drug.

U.S. Pat. No. 5,968,554 to Beiman et al. discloses a delivery systemthat contains a core comprising an active pharmaceutical, an enteralcoating over the core comprising a pH dependent water soluble polymer, asecond coating of the active pharmaceutical, and thereafter a coatingthat is soluble in gastric juices.

U.S. Pat. No. 5,162,117 to Schering Corporation describes a two pulsetablet of flutamide designed to provide an immediate release dose and asecond delayed dose in pulsatile manner in the gastrointestinal tract.The first pulse is contained in an immediate release layer while thesecond pulse is obtained from a core which contains a solid dispersionof the flutamide in a carrier. The pulses are separated by a film layerof an enteric coating at 4-15% weight percent of the core.

U.S. Pat. Nos. 6,238,699 and 6,756,056 disclose an oral antiparkinsondrug delivery system consisting of carbidopa and levodopa in immediateand sustained release compartments. An outer layer comprising animmediate release composition comprising carbidopa and levodopa isseparated by an intermediate excipient layer from a core layercomprising a sustained release composition comprising carbidopa andlevodopa.

Other patents disclosing a controlled release dose form containinglevodopa and carbidopa which requires immediate release and controlledrelease components include U.S. Pregrant Patent Application PublicationsNo. 20030224045, No. 20030228360, No. 20030031707, and No. 20040166159,and the PCT International Publication No. WO 00/15197.

Multi-layered osmotic devices that provide a controlled release of drugfrom a core and a rapid/immediate release of drug from an externalcoating are known. U.S. Pat. No. 6,004,582, U.S. Pat. No. 6,521,255,U.S. Pat. No. 6,569,456, U.S. Pat. No. 6,572,890, U.S. Pat. No.6,599,532, U.S. Pat. No. 6,605,302, U.S. Pat. No. 6,613,357, and the PCTInternational Publications No. WO04/056335 and No. WO04/087095 toOsmotica Corp. disclose various embodiments of a multi-layered osmoticdevice, wherein an osmotic core is surrounded by an immediate or rapidrelease drug-containing composition.

Thombre et al. (J. Controlled Release 94(1), 75-89, 2004) disclose anosmotic device having a monolithic, bi-layered or tri-layered core.

U.S. Pat. No. 4,576,604 to Alza Corporation discloses several differentembodiments of an osmotic device having a drug in the core and at leastone lamina surrounding the core.

U.S. Pat. No. 4,801,461 to Alza Corporation discloses an osmotic dosageform comprising pseudoephedrine in the core, a semipermeable wallsurrounding the core comprising varying amounts of cellulose acetate orcellulose triacetate and varying amounts of hydroxypropylcellulose, apassageway in the wall for delivering the drug from the core and,optionally, a lamina on the outside of the wall comprisingpseudoephedrine.

U.S. Pat. No. 4,810,502 to Alza Corporation discloses an osmotic dosageform for delivering pseudoephedrine (Ps) and brompheniramine (Br) whichcomprises a core containing Ps and Br, a wall surrounding the corecomprising cellulose acylate and hydroxypropylcellulose, a passageway inthe wall for delivering the drug, and a lamina on the outside of thewall comprising Ps, BR, at least one of hydroxypropylcellulose orhydroxypropyl methylcellulose, and poly(ethylene oxide) for enhancingthe mechanical integrity and pharmacokinetics of the wall.

U.S. Pat. No. 5,057,321, and U.S. Pat. No. 5,128,145 to Alza Corporationdisclose a dosage form comprising a wall surrounding a compartment, thewall comprising at least in part a semipermeable polymeric compositionpermeable to the passage of fluid and substantially impermeable to thepassage of drug, a layer in the compartment comprising a formulationcomprising a dosage unit amount of a drug for performing a therapeuticprogram and a maltodextrin, a layer in the compartment comprising anosmotic formulation for imbibing, and absorbing fluid for expanding insize for pushing the drug maltodextrin formulation from the dosage form,and at least one passageway in the wall for releasing the drug. In oneembodiment an immediate release lamina is compressed or air sprayedaround the external surface of the delivery device to yield an immediaterelease coat.

U.S. Pat. No. 5,190,763, U.S. Pat. No. 5,192,550, U.S. Pat. No.5,221,536 and U.S. Pat. No. 6,217,905 to Alza Corporation disclose adosage form comprising: a wall surrounding a compartment, the wallcomprising at least in part a semipermeable polymeric compositionpermeable to the passage of fluid and substantially impermeable to thepassage of an anti-Parkinson drug; a layer in the compartment comprisinga formulation comprising a dosage unit amount of an anti-Parkinson drugfor performing a therapeutic program; a layer in the compartmentcomprising an osmotic formulation for imbibing and absorbing fluid forpushing the anti-Parkinson formulation from the dosage form; and, atleast one passageway in the wall for releasing the anti-Parkinson drug.In one embodiment an immediate release lamina is compressed or airsprayed around the external surface of the delivery device to yield animmediate release coat.

U.S. Pat. No. 5,558,879 to Andrx Pharmaceuticals discloses a controlledrelease tablet for water soluble drugs in which a passageway is formedin the environment of use, i.e., the GI tract of a person receiving theformulation. The controlled release tablet consists of a core, a duallayer membrane coating around the core, and an outer immediate releasecoating containing a drug and a water soluble polymer.

U.S. Pat. No. 5,681,584 to Alza Corporation discloses a controlledrelease drug delivery device comprising a core containing a drug, anoptional osmotic agent and optional excipients, a delayed release jacketcomprising at least one of a binder, an osmotic agent and a lubricantsurrounding the core, a semipermeable membrane surrounding the delayedrelease jacket and optionally having a passageway, a drug containinglayer either on the outside of the semipermeable membrane or between thesemipermeable membrane and the delayed release jacket, and an optionalenteric coat either on the outside of the drug-containing layer, betweenthe drug-containing layer and the semipermeable membrane or on theoutside of the semipermeable membrane when the drug-containing layer isbetween the delayed release jacket and the semipermeable membrane.

U.S. Pregrant Patent Application Publication No. 20050025831 to AlzaCorporation discloses an osmotic dosage form comprising a longitudinallycompressed tablet core containing a plurality of layers wherein a drugis contained in at least one layer and at least one other layercomprises a suitable fluid-expandable polymer, a semipermeable wallsurrounding said longitudinally compressed tablet core to thereby form acompartment having an osmotic gradient to drive fluid from an externalfluid environment contacting said semipermeable wall into saidcompartment, and an orifice formed through said semipermeable wall andinto said longitudinally compressed tablet core to permit drug to bereleased from within said compartment into said external fluidenvironment. The dosage forms may additionally comprise animmediate-release dose of drug.

U.S. Pat. No. 6,544,554 to Chugai Seiyaku Kabushiki Kaisha discloses aformulation that has a drug core surrounded by a release control layerto present a mechanism by which the drug in the core is rapidly releasedafter a predetermined delay in time. The formulation also has a rapiddrug release portion provided outside the release control layer so thatthe drug can be released more than once at intervals after singledosing. Further in addition, the invention relates to a formulation thatincorporates a plurality of drugs in both a core and one or more drugrelease layers so that different active ingredients can be released atdifferent times.

While the prior art discloses a wide variety of oral multi-layeredtablets, none of the prior art discloses a multi-layered tablet for atriple combination release of active agents to an environment of use.Thus, there is a need for a drug delivery system that provides a triplecombination release of at least one active agent. Such a system couldimprove patient compliance to a drug regimen or offer opportunities oftreatment otherwise not attainable.

SUMMARY OF THE INVENTION

The present invention seeks to provide an improvement upon the relateddosage forms known in the art.

Some embodiments of the invention provide a multi-layered tabletcomprising two external drug-containing layers in stacked arrangementwith respect to and on opposite sides of an oral dosage form such thatthe tablet provides a triple combination release of at least one activeagent.

Another aspect of the invention provides a multi-layered tabletcomprising two external drug-containing layers in stacked arrangementwith respect to and on opposite sides of an osmotic device comprising acore coated with a semipermeable membrane having at least one preformedpassageway through it.

A combination release tablet comprising: a) a drug-containing rapidrelease first compressed composition comprising at least one drug; b) adrug-containing extended release second compressed compositioncomprising at least one drug and a release rate modifier; and c) apreformed and film-coated extended release intermediate drug-containingcomposition comprising a drug-containing core surrounded by a coating;wherein the first compressed composition and second compressedcomposition oppose one another, are in direct contact with, in stackedarrangement with respect to, and disposed on opposite faces or surfacesof the intermediate drug-containing composition, whereby the tabletprovides three different active agent release profiles.

The preformed and film-coated extended release intermediatedrug-containing composition can be an osmotic device comprising a coresurrounded by a membrane having a preformed passageway through it. Themembrane can be a semipermeable membrane, a microporous membrane, or animpermeable membrane. Depending upon how the osmotic device ismanufactured, the preformed passageway may or may not be plugged. Whenthe preformed passageway is plugged by the first or second compressedcomposition, initial release of drug from the core is delayed for atleast a period of about 10 min.

The preformed and film-coated extended release intermediatedrug-containing composition can be a capsule comprising a shellenclosing a drug-containing composition. The shell may or may notcomprise at least one preformed passageway. The shell can be erodible,swellable, degradable and/or soluble in aqueous medium. Thedrug-containing composition within the shell optionally comprises arelease rate modifier, if not, the shell is a release rate-controllingshell.

The preformed and film-coated extended release intermediatedrug-containing composition can be a gastro-resistant coated corecomprising a gastro-resistant coating surrounding a drug-containingcomposition. The core can comprise a release rate-controlling material.A gastro-resistant coated core is adapted for release of drug downstreamof the gastric region following oral administration of the tablet to asubject. For example, the gastro-resistant coated core can be adaptedfor release of drug in the intestine or colon following oraladministration of the tablet to a subject.

The multi-layered tablet comprises one drug or two, three, four or moredifferent drugs. At each occurrence, the identity of the drug in a layeris independently selected from any pharmaceutically acceptable drug. Forexample, each drug-containing composition can comprise a drug differentfrom the drug in any other drug-containing composition present.Alternatively, two drug-containing compositions can comprise the samedrug and the third drug-containing compositions can comprise a differentdrug. In another embodiment, a drug in the first compressed compositionis different than a drug in the second compressed composition,optionally, wherein a drug in the first compressed composition isdifferent than a drug in the drug-containing core, optionally, wherein adrug in the second compressed composition is different than a drug inthe drug-containing core. In another embodiment, a drug in the firstcompressed composition is the same as a drug in the drug-containingcore. In still another embodiment, the first compressed compositioncomprises two different drugs, the core comprises a third differentdrug, and the second compressed composition comprises a charge of eitherone of the three different drugs. Another embodiment provides the firstcompressed composition comprising a charge of each of two differentdrugs, the core comprising a charge of the third different drug, and thesecond compressed composition comprising an additional charge of eitherone of the three different drugs. In other embodiments, two or three ofthe drug-containing compositions comprise the same drug. When two of thedrug-containing compositions have the same drug, the thirddrug-containing composition will have a drug that is the same as ordifferent than the drug in the other two compositions.

Each drug-containing composition can independently comprise more thanone drug. For example, a first drug-containing composition can have twodifferent drugs, while the remaining second drug-containing compositioncan comprise a third different drug or it can comprise a drug that isthe same as one of the drugs in the first drug-containing composition.

Another aspect of the invention provides a multi-layered tabletcomprising two external drug-containing layers in stacked arrangementwith respect to and on opposite sides of a gastro-resistant coated core.

Yet another aspect of the invention provides an oral dosage form thatprovides a multi-layered tablet comprising two external drug-containinglayers in stacked arrangement with respect to and on opposite sides of ahard capsule.

In some embodiments of the invention, the first external drug-containinglayer releases the drug in an immediate/rapid form, the second externaldrug-containing layer releases the drug in an extended form, and theosmotic device, gastro-resistant coated core or hard capsule releasesthe drug in an extended form.

In other embodiments, the release of the drug from the osmotic core willbegin after the preformed passageway is no longer plugged by theexternal drug-containing layer if the preformed passageway is madebefore the external drug-containing layers have been formed. Thelocation and size of the preformed passageway in the osmotic device isvaried as needed to provide the desired impact upon drug release. Insome embodiments, the preformed passageway is adjacent the externalextended release layer or the external immediate/rapid release layer.The preformed passageway can be made before or after the externaldrug-containing layer(s) has (have) been formed. The delayed period forinitiation of the release will depend upon whether the preformedpassageway is adjacent the immediate/rapid release layer or the extendedrelease layer and upon whether or not the preformed passageway has beenformed before or after attachment of the external layer(s).

Other embodiments of the invention include those wherein one of theexternal drug-containing layers releases the drug in an immediate/rapidform, the other external drug-containing layer releases the drug in anextended form, and the gastro-resistant coated core releases the drug ina delayed and extended form. In other embodiments, one of the externaldrug-containing layers releases the drug in an immediate/rapid form, theother external drug-containing layer releases the drug in an extendedform, and the gastro-resistant coated core releases the drug in adelayed and rapid form.

The external drug-containing layers can be applied onto the intermediatedrug-containing formulation by compression.

Combinations of the various embodiments disclosed herein are consideredwithin the scope of the invention. Other features, advantages andembodiments of the invention will become apparent to those skilled inthe art by the following description, accompanying examples.

BRIEF DESCRIPTION OF THE FIGURES

The following drawings are part of the present specification and areincluded to further demonstrate certain aspects of the invention. Theinvention may be better understood by reference to one or more of thesedrawings in combination with the detailed description of the specificembodiments presented herein.

FIG. 1 depicts a cross-sectional view of a multi-layered tabletcomprising two external drug-containing layers in stacked arrangementwith respect to and on opposite sides of an intermediate drug-containingformulation.

FIG. 2 depicts a cross-sectional view of a multi-layered tabletcomprising two external drug-containing layers in stacked arrangementwith respect to and on opposite sides of an osmotic device comprising acore coated with a semipermeable membrane having a preformed passagewaythrough it.

FIG. 3 depicts a cross-sectional view of a multi-layered tabletcomprising two external drug-containing layers in stacked arrangementwith respect to and on opposite sides of a gastro-resistant coated core.

FIG. 4 depicts a partial cross-sectional view of a multi-layered tabletcomprising two external drug-containing layers in stacked arrangementwith respect to and on opposite sides of a hard capsule.

FIG. 5 depicts the in vitro release profile of amantadine from theexemplary multi-layered tablet of Example 1.

FIG. 6 depicts the in vitro release profile of levodopa from theexemplary multi-layered tablet of Example 1.

FIG. 7 depicts the in vitro release profile of carbidopa from theexemplary multi-layered tablet of Example 1.

FIG. 8 depicts the in vitro release profile of amantadine from theexemplary multi-layered tablet of Example 2.

FIG. 9 depicts the in vitro release profile of levodopa from theexemplary multi-layered tablet of Example 2.

FIG. 10 depicts the in vitro release profile of carbidopa from theexemplary multi-layered tablet of Example 2.

FIG. 11 depicts the in vitro release profile of amantadine from theexemplary multi-layered tablet of Example 7.

FIG. 12 depicts the in vitro release profile of levodopa from theexemplary multi-layered tablet of Example 7.

FIG. 13 depicts the in vitro release profile of carbidopa from theexemplary multi-layered tablet of Example 7.

FIG. 14 depicts the in vitro release profile of venlafaxine from theexemplary multi-layered tablet of Example 3.

FIG. 15 depicts the in vitro release profile of ondensetron from theexemplary multi-layered tablet of Example 3.

FIG. 16 depicts the in vitro release profile of alprazolam from theexemplary multi-layered tablet of Example 3.

FIG. 17 depicts the in vitro release profile of venlafaxine from theexemplary multi-layered tablet of Example 8.

FIG. 18 depicts the in vitro release profile of ondensetron from theexemplary multi-layered tablet of Example 8.

FIG. 19 depicts the in vitro release profile of alprazolam from theexemplary multi-layered tablet of Example 8.

FIG. 20 depicts the in vitro release profile of ropinirole from theexemplary multi-layered tablet of Example 4.

FIG. 21 depicts the in vitro release profile of levodopa from theexemplary multi-layered tablet of Example 4.

FIG. 22 depicts the in vitro release profile of carbidopa from theexemplary multi-layered tablet of Example 4.

FIG. 23 depicts the in vitro release profile of venlafaxine from theexemplary multi-layered tablet of Example 5.

FIG. 24 depicts the in vitro release profile of ondensetron from theexemplary multi-layered tablet of Example 5.

FIG. 25 depicts the in vitro release profile of quetiapene from theexemplary multi-layered tablet of Example 5.

FIG. 26 depicts the in vitro release profile of lithium from theexemplary multi-layered tablet of Example 6.

FIG. 27 depicts the in vitro release profile of quetiapene from theexemplary multi-layered tablet of Example 6.

FIG. 28 depicts the in vitro release profile of divalproex sodium fromthe exemplary multi-layered tablet of Example 6.

FIG. 29 depicts the in vitro release profile of entacapone from theexemplary multi-layered tablet of Example 9.

FIG. 30 depicts the in vitro release profile of levodopa from theexemplary multi-layered tablet of Example 9.

FIG. 31 depicts the in vitro release profile of carbidopa from theexemplary multi-layered tablet of Example 9.

FIG. 32 depicts the in vitro release profile of entacapone from theexemplary multi-layered tablet of Example 10.

FIG. 33 depicts the in vitro release profile of levodopa from theexemplary multi-layered tablet of Example 10.

FIG. 34 depicts the in vitro release profile of carbidopa from theexemplary multi-layered tablet of Example 10.

FIG. 35 depicts the in vitro release profile of domperidone from theexemplary multi-layered tablet of Example 11

FIG. 36 depicts the in vitro release profile of ergotamine from theexemplary multi-layered tablet of Example 11

FIG. 37 depicts the in vitro release profile of naproxen from theexemplary multi-layered tablet of Example 11

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a multi-layered tablet that possesses atriple combination release of active agents when placed in anenvironment of use.

The invention may be better understood by reference to the followingdefinitions provided herein.

The term “intermediate drug-containing formulation” is employed hereinto refer to a film-coated composition, an osmotic device, a coatedtablet, a gastro-resistant coated core, a hard capsule, agastro-resistant coated caplet, and other similar or equivalent dosageforms known to those of ordinary skill in the art.

The term “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

A “therapeutically effective amount” is the amount or quantity of drug,which is sufficient to elicit the required or desired therapeuticresponse, or in other words, the amount that is sufficient to elicit anappreciable biological response when administered to a patient.

By “immediate release” (IR) is meant a release of an active agent to anenvironment over a period of seconds to no more than about 30 minutesonce release has begun and release begins within a second to no morethan about 15 minutes after exposure to an aqueous environment. Animmediate release composition, which does not possess a substantialdelay in drug release, should be considered a subset of a rapid releasecomposition. An immediate release composition releases drug in thebuccal cavity, esophagus and/or stomach.

By “rapid release” (RR) is meant a release of an active agent to anenvironment over a period of seconds to no more than about 59 minutesonce release has begun and release can begin within a few seconds orminutes after exposure to an aqueous environment or after expiration ofa delay period (lag time) after exposure to an aqueous environment. Ingeneral, a rapid release composition releases drug releases drug in thestomach, jejunum or duodenum after oral administration, provided thecomposition does not include a delayed release material or delayedrelease coating. In such a case, the rapid release composition wouldrelease drug in the upper, middle and/or lower intestine or colon.

By “extended release” (ER) is meant a controlled release of an activeagent from a dosage form to an environment over (throughout or during)an extended period of time, e.g. greater than or equal to one hour. Asused herein, the term “extended release” profile assumes the definitionas widely recognized in the art of pharmaceutical sciences. An extendedrelease dosage form will release drug at substantially constant rateover an extended period of time or a substantially constant amount ofdrug will be released incrementally over an extended period of time. Theterm “extended release”, as regards to drug release, includes the terms“controlled release”, “prolonged release”, “sustained release”, or “slowrelease”, as these terms are used in the pharmaceutical sciences.

By “controlled release” (CR) is meant a release of an active agent to anenvironment over a period of about eight hours up to about 12 hours, 16hours, 18 hours, 20 hours, a day, or more than a day. A controlledrelease can begin within a few minutes after exposure to an aqueousenvironment or after expiration of a delay period (lag time) afterexposure to an aqueous environment.

By “sustained release” (SR) is meant a controlled release of an activeagent to maintain a constant drug level in the blood or target tissue ofa subject to which the pharmaceutical composition is administered.

As used herein, a “dosage form” is a solid dosage form containing thepharmaceutical composition of the invention and being suitable for oraladministration to a patient (subject).

A “zero-order” release profile characterizes the release profile of adosage form that releases a constant amount of drug per unit time. A“pseudo-zero order” release profile is one that approximates azero-order release profile.

A “first order” release profile characterizes the release profile of adosage form that releases a constant percentage of an initial drugcharge per unit time. A “pseudo-first order” release profile is one thatapproximates a first order release profile.

A “delayed but controlled or extended release dosage form” is one thatprovides a delayed release of a drug followed by a controlled orextended release of the drug. By “delayed release” (DR) is meant anyformulation technique wherein release of the active substance from thedosage form is modified to occur at a later time than that from aconventional immediate release product. In other words, the beginning ofthe controlled release of drug is delayed by an initial period of time.The period of delay is generally about 5 minutes to 10 hours, or 30minutes to 5 hours, or 1 hour to 3 hours.

As used herein, the term “release rate-controlling coating” refers to acoating surrounding a tablet that controls the rate of release of drugfrom an associated composition such that the drug is releasedsubstantially continuously over an extended period of time. A releaserate-controlling coating is not a delayed release coating, since adelayed release coating does not control the rate of drug release. Adelayed release coating merely delays the initial release of drug froman associated composition.

FIG. 1 depicts a multi-layered tablet (1) comprising two externaldrug-containing layers (3 and 4) in stacked arrangement with respect toand on opposite sides of an intermediate drug-containing formulation(2). The multi-layered tablet provides a triple combination release ofat least one active agent. By “triple combination release” is meant thatthe multi-layered tablet provides three different drug release profilesfor an active agent. In other words, each layer of the multi-layeredtablet has its own drug release profile, or each of the three drugrelease profiles in a single multi-layered tablet is different than theother two. The rapid or immediate release layer (4) opposes and contactsthe extended release layer (3). The intermediate drug-containingformulation is a controlled release dosage form in some embodiments.

The intermediate drug-containing formulation can be an osmotic device.FIG. 2 depicts a multi-layered tablet (5) comprising two externaldrug-containing layers (10 and 11) in stacked arrangement with respectto and on opposite sides of an osmotic device (6) comprising a core (7)coated with a semipermeable membrane (8) having a preformed passageway(9) through it. In one embodiment, one of the external drug-containinglayers (11) releases the drug in an immediate/rapid form, the otherexternal drug-containing layer (10) releases the drug in an extendedform, and the osmotic device releases the drug in a controlled form, asdisclosed in Examples 1, 3, 4, 5 and 6. The preformed passageway can beadjacent the extended release layer or the immediate/rapid releaselayer. The preformed passageway can be made before or after the externaldrug-containing layers have been formed. The release of the drug fromthe osmotic core will begin after the external drug-containing layer nolonger plugs the preformed passageway if the preformed passageway ismade before the external drug-containing layers have been formed. Thedelayed period for initiation of the release will depend upon whetherthe preformed passageway is adjacent the immediate/rapid release layeror the extended release layer and upon whether or not the preformedpassageway has been formed before or after attachment of the externallayer(s).

Release of drug from the core of the osmotic device is delayed until thepreformed passageway in the semipermeable membrane is uncovered orunplugged by any material superposing it. When the preformed passagewayis adjacent the rapid or immediate release external layer but does notpass through the layer, and the osmotic device does not contain adelayed release composition, then release of drug from the core canbegin shortly after the external layer has dissolved and/or erodedsufficiently to uncover the preformed passageway, e.g. 10, 20, or 30minutes after placement of the device in an environment of use. When thepreformed passageway is adjacent the extended release external layer butdoes not pass through the layer, and the osmotic device does not containa delayed release composition, then release of drug from the core can bedelayed and can begin shortly after the external layer has dissolvedand/or eroded sufficiently to uncover the preformed passageway, e.g. atleast 60 minutes after placement of the device in an environment of use.When the preformed passageway passes through an external layersuperposing it, the release of drug from the core can begin shortly,e.g. 5 minutes after placement of the device in an environment of use.

FIG. 3 depicts a multi-layered tablet (15) comprising two externaldrug-containing layers (19 and 20) in stacked arrangement with respectto and on opposite sides of a gastro-resistant coated core (16). In oneembodiment, one of the external drug-containing layers (20) releases thedrug in an immediate/rapid form, the other external drug-containinglayer (19) releases the drug in an extended form, and thegastro-resistant coated core (16) releases the drug in a delayed andextended form, as disclosed in Examples 2, 9 and 10, due to thegastro-resistant coating (18) surrounding the drug-containing core (17).

As used herein, a “gastro-resistant coated core” refers to a coatedcomposition, wherein, after oral administration to a subject, thecoating retains its integrity for a sufficient period of time to delayrelease of drug from the core until after the core has exited thegastric region. Materials suitable for use in making the coating of agastro-resistant coated core are described herein.

FIG. 4 depicts a multi-layered tablet (25) comprising two externaldrug-containing layers (27 and 28) in stacked arrangement with respectto and on opposite sides of a hard capsule (26). In one embodiment, oneof the external drug-containing layers (28) releases the drug in animmediate/rapid form, the other external drug-containing layer (27)releases the drug in an extended form, and the hard capsule releases thedrug in a controlled form, as disclosed in Example 8.

A capsule comprises a drug-containing composition enclosed within acapsule shell, which can be made of any material typically used formaking such a shell. The term “shell” as used herein is taken to meanthe shell of a capsule dosage form or the encasement or encapsulationmaterial used to encapsulate fill compositions. Any material suitablefor use in forming a capsule shell or in encapsulating anothercomposition can be used according to the invention. An aqueouscomposition according to the invention is surrounded by a water (oraqueous medium) erodible, soluble, swellable and/or degradable shell orencapsulating material.

Materials suitable for the preparation of the capsule shell include byway of example and without limitation gelatin, hydroxypropylmethylcellulose, starch, animal gelatin, agar, fish (piscine) gelatin ora combination thereof. Other suitable materials include: polyvinylalcohol/polyvinyl acetate copolymer (U.S. Pat. No. 3,300,546); a blendof hydroxybutyl methylcellulose and hydroxypropyl methylcellulose (U.S.Pat. No. 4,765,916); polyvinyl acetate (U.S. Pat. No. 2,560,649, U.S.Pat. No. 3,346,502); water-soluble gelatin (U.S. Pat. No. 3,525,426);polyvinyl alcohol (U.S. Pat. No. 3,528,921, U.S. Pat. No. 3,534,851,U.S. Pat. No. 3,556,765, U.S. Pat. No. 3,634,260, U.S. Pat. No.3,671,439, U.S. Pat. No. 3,706,670, U.S. Pat. No. 3,857,195, U.S. Pat.No. 3,877,928, U.S. Pat. No. 4,367,156, U.S. Pat. No. 4,747,976, U.S.Pat. No. 5,270,054); polymers derived from such monomers as vinylchloride, vinyl alcohol, vinyl pyrrolidone, furan, acrylonitrile, vinylacetate, methyl acrylate, methyl methacrylate, styrene, vinyl ethylether, vinyl propyl ether, acrylamide, ethylene, propylene, acrylicacid, methacrylic acid, maleic anhydride, salts of any of theaforementioned acids and mixtures thereof; polyvinyl chloride;polypropylene; acrylic/maleic copolymers; sodium polyacrylate; polyvinylpyrrolidone; glucomannan and optionally another natural polysaccharidewith a polyhydric alcohol such as glycerin (U.S. Pat. No. 4,851,394);plastic and polylactide/polyglycolide (Elanco Animal Health Co.); HPMC(Shionogi Qualicaps Co. Ltd (Nara Japan); SUHEUNG CAPSULES CO. LTD.(KYUNGGI-DO, KOREA) and Capsugel); or a combination thereof. Essentiallyany material known to those of ordinary skill in the art as being forthe preparation of capsule shell can be used in a capsule according tothe invention. Suitable starch capsules can be made and used accordingto Vilivalam et al. (Pharmaceutical Science & Technology Today (2000), 3(2), 64-69). A chitosan capsule for colonic delivery can be made andused according to Yamamoto (Kobunshi (1999), 48 (8), 595) or Tozaki etal. (Drug Delivery System (1997), 12 (5), 311-320).

The tableting machines useful to manufacture the multi-layered tabletsof the invention have two powder filling positions and one internal coredispenser/centering device, such as for example the Fette machine model4090, Kilian-Centra-Cota kind or Korsch-Central Core Coater 3C. Thesemachines are able to take said cores, place and center them correctlyinto the die where the granulate is filled for the partial coating ofsaid core. The dispenser can be adapted to dispense different dosageforms.

Some embodiments of the invention limit the intermediate drug-containingcomposition to a film-coated composition, e.g. an osmotic device, acapsule, a coated core, and the two external drug-containing layers,applied to the film-coated composition, to compressed layers. The filmof the film-coated composition can be applied by spray-coating, such asfor an osmotic device or a coated core, or it can be preformed, such asa capsule shell.

The present inventors have developed a process whereby a film-coatedcomposition can be coated with two separated compressed compositionswithout rupturing the film of the film-coated composition during thecompression steps. Thus, a multi-layered tablet is prepared by a processcomprising:

-   providing a drug-containing rapid release or extended release    composition and compressing said composition in a die with a convex    punch to form a compressed concave composition;-   providing a preformed intermediate drug-containing composition and    placing it on the compressed concave composition in the die;-   placing a drug-containing extended release or rapid release    composition, respectively, over the intermediate drug-containing    composition and compressing it with a punch, thereby forming the    multi-layered tablet.

The compression surface of the punch can be flat, convex, concave or acombination thereof. When a flat compression surface is used, theresulting compressed composition will have a flat mating surface. When aconvex compression surface is used, the resulting compressed compositionwill have a concave mating surface. When a concave compression surfaceis used, the resulting compressed composition will have a convex matingsurface. The multi-layered tablet of FIG. 3 is made using a flat punch.The multi-layered tablet of FIG. 2 is made using a convex punch. Themulti-layered tablets of FIGS. 1 and 4 is made using a punch having acombination flat and convex surface.

By virtue of the process employed in making the multi-layered tablet,the external layers are not concentric. Instead, they are in stackedarrangement with respect to each other and the intermediatedrug-containing composition, and they oppose each other, meaning theyare located on opposite sides, ends or faces of the intermediatedrug-containing composition. The external compressed layers may (FIGS.1, 4) or may not (2, 3) contact each other. The invention also includesembodiments that are combinations of the multi-layered tablets depictedin FIGS. 1-4.

The pharmaceutical compositions comprise in the multi-layered tablet ofthe invention can include a wide range of different excipients. Suitabletypes of excipients include adsorbents, antioxidants, acidifying agent,alkalizing agent, buffering agents, colorants, flavorants, sweeteningagents, tablet antiadherents, tablet binders, tablet diluents, tabletdirect compression excipients, tablet disintegrants, tablet glidants,tablet lubricants, tablet opaquants and/or tablet polishing agents.Similar excipients used in capsule formulations can also be include inthe multi-layered tablet of the invention.

As used herein, the term “alkalizing agent” is intended to mean acompound used to provide alkaline medium for product stability. Suchcompounds include, by way of example and without limitation, ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodiumbicarbonate, sodium hydroxide, triethanolamine, diethanolamine, organicamine base, alkaline amino acids and trolamine and others known to thoseof ordinary skill in the art.

As used herein, the term “acidifying agent” is intended to mean acompound used to provide an acidic medium for product stability. Suchcompounds include, by way of example and without limitation, aceticacid, acidic amino acids, citric acid, fumaric acid and other alphahydroxy acids, hydrochloric acid, ascorbic acid, phosphoric acid,sulfuric acid, tartaric acid and nitric acid and others known to thoseof ordinary skill in the art.

As used herein, the term “adsorbent” is intended to mean an agentcapable of holding other molecules onto its surface by physical orchemical (chemisorption) means. Such compounds include, by way ofexample and without limitation, powdered and activated charcoal andother materials known to one of ordinary skill in the art.

As used herein, the term “antioxidant” is intended to mean an agent thatinhibits oxidation and thus is used to prevent the deterioration ofpreparations by the oxidative process. Such compounds include, by way ofexample and without limitation, ascorbic acid, ascorbyl palmitate,butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorousacid, monothioglycerol, propyl gallate, sodium ascorbate, sodiumbisulfite, sodium formaldehyde sulfoxylate and sodium metabisulfite andother materials known to one of ordinary skill in the art.

As used herein, the term “buffering agent” is intended to mean acompound used to resist change in pH upon dilution or addition of acidor alkali. Such compounds include, by way of example and withoutlimitation, potassium metaphosphate, potassium phosphate, monobasicsodium acetate and sodium citrate anhydrous and dihydrate and othermaterials known to one of ordinary skill in the art.

As used herein, the term “sweetening agent” is intended to mean acompound used to impart sweetness to a preparation. Such compoundsinclude, by way of example and without limitation, aspartame, dextrose,glycerin, mannitol, saccharin sodium, sorbitol and sucrose and othermaterials known to one of ordinary skill in the art.

As used herein, the term “antiadherent” is intended to mean an agentthat prevents the sticking of tablet formulation ingredients to punchesand dies in a tableting machine during production. Such compoundsinclude, by way of example and without limitation, magnesium stearate,talc, calcium stearate, glyceryl behenate, polyethylene glycol (PEG),hydrogenated vegetable oil, mineral oil, stearic acid and othermaterials known to one of ordinary skill in the art.

As used herein, the term “binder” is intended to mean a substance usedto cause adhesion of powder particles in granulations. Such compoundsinclude, by way of example and without limitation, acacia, alginic acid,carboxymethylcellulose sodium, poly(vinylpyrrolidone), compressiblesugar (e.g., NuTab), ethylcellulose, gelatin, liquid glucose,methylcellulose, povidone and pregelatinized starch and other materialsknown to one of ordinary skill in the art.

Exemplary binders include acacia, tragacanth, gelatin, starch, cellulosematerials such as methyl cellulose and sodium carboxy methyl cellulose,alginic acids and salts thereof, polyethylene glycol, guar gum,polysaccharide, bentonites, sugars, invert sugars, poloxamers (PLURONIC™F68, PLURONIC™ F127), collagen, albumin, gelatin, cellulosics innonaqueous solvents, combinations thereof and the like. Other bindersinclude, for example, polypropylene glycol,polyoxyethylene-polypropylene copolymer, polyethylene ester,polyethylene sorbitan ester, polyethylene oxide, combinations thereofand other materials known to one of ordinary skill in the art.

As used herein, the term “diluent” or “filler” is intended to mean inertsubstances used as fillers to create the desired bulk, flow properties,and compression characteristics in the preparation of tablets andcapsules. Such compounds include, by way of example and withoutlimitation, dibasic calcium phosphate, kaolin, lactose, sucrose,mannitol, microcrystalline cellulose, powdered cellulose, precipitatedcalcium carbonate, sorbitol, and starch and other materials known to oneof ordinary skill in the art.

As used herein, the term “direct compression excipient” is intended tomean a compound used in direct compression tablet formulations. Suchcompounds include, by way of example and without limitation, dibasiccalcium phosphate (e.g., Ditab) and other materials known to one ofordinary skill in the art.

As used herein, the term “glidant” is intended to mean an agent used intablet and capsule formulations to promote flowability of thegranulation. Such compounds include, by way of example and withoutlimitation, colloidal silica, cornstarch, talc, calcium silicate,magnesium silicate, colloidal silicon, silicon hydrogel and othermaterials known to one of ordinary skill in the art.

As used herein, the term “lubricant” is intended to mean a substanceused in the instant formulations to reduce friction during compressionor other processing. Such compounds include, by way of example andwithout limitation, calcium stearate, magnesium stearate, mineral oil,stearic acid, and zinc stearate and other materials known to one ofordinary skill in the art.

As used herein, the term “opaquant” is intended to mean a compound usedto render a capsule or a tablet coating opaque. May be used alone or incombination with a colorant. Such compounds include, by way of exampleand without limitation, titanium dioxide, talc and other materials knownto one of ordinary skill in the art.

As used herein, the term “polishing agent” is intended to mean acompound used to impart an attractive sheen to coated tablets. Suchcompounds include, by way of example and without limitation, carnaubawax, white wax and other materials known to one of ordinary skill in theart.

As used herein, the term “disintegrant” is intended to mean a compoundused in solid dosage forms to promote the disruption of the solid massinto smaller particles that are more readily dispersed or dissolved.Exemplary disintegrants include, by way of example and withoutlimitation, starches such as corn starch, potato starch, pre-gelatinizedand modified starches thereof, sweeteners, clays, such as bentonite,microcrystalline cellulose (e.g., Avicel), carboxymethylcellulosecalcium, cellulose polyacrilin potassium (e.g., Amberlite), alginates,sodium starch glycolate, gums such as agar, guar, locust bean, karaya,pectin, tragacanth; crospovidone and other materials known to one ofordinary skill in the art.

As used herein, the term “colorant” is intended to mean a compound usedto impart color to solid (e.g., tablets) pharmaceutical preparations.Such compounds include, by way of example and without limitation, FD&CRed No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&CGreen No. 5, D&C Orange No. 5, D&C Red No. 8, caramel, and ferric oxide,red, other F.D. & C. dyes and natural coloring agents such as grape skinextract, beet red powder, beta-carotene, annato, carmine, turmeric,paprika, and other materials known to one of ordinary skill in the art.The amount of coloring agent used will vary as desired.

As used herein, the term “flavorant” is intended to mean a compound usedto impart a pleasant flavor and often odor to a pharmaceuticalpreparation. Exemplary flavoring agents or flavorants include syntheticflavor oils and flavoring aromatics and/or natural oils, extracts fromplants, leaves, flowers, fruits and so forth and combinations thereof.These may also include cinnamon oil, oil of wintergreen, peppermintoils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaveoil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil.Other useful flavors include vanilla, citrus oil, including lemon,orange, grape, lime and grapefruit, and fruit essences, including apple,pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot andso forth. Flavors that have been found to be particularly useful includecommercially available orange, grape, cherry and bubble gum flavors andmixtures thereof. The amount of flavoring may depend on a number offactors, including the organoleptic effect desired. Flavors will bepresent in any amount as desired by those of ordinary skill in the art.Particular flavors are the grape and cherry flavors and citrus flavorssuch as orange.

The present multi-layered tablet can also employ one or more commonlyknown surface-active agents or cosolvents that improve wetting ordisintegration of the tablet core or layers.

Plasticizers can also be included in the multi-layered tablet of theinvention to modify the properties and characteristics of the polymersused in the coats or core of the tablet. As used herein, the term“plasticizer” includes all compounds capable of plasticizing orsoftening a polymer or binder used in invention. The plasticizer shouldbe able to lower the melting temperature or glass transition temperature(softening point temperature) of the polymer or binder. Plasticizers,such as low molecular weight PEG, generally broaden the averagemolecular weight of a polymer in which they are included therebylowering its glass transition temperature or softening point.Plasticizers also generally reduce the viscosity of a polymer. It ispossible the plasticizer will impart some particularly advantageousphysical properties to the osmotic device of the invention.

Plasticizers useful in the invention can include, by way of example andwithout limitation, low molecular weight polymers, oligomers,copolymers, oils, small organic molecules, low molecular weight polyolshaving aliphatic hydroxyls, ester-type plasticizers, glycol ethers,poly(propylene glycol), multi-block polymers, single block polymers, lowmolecular weight poly(ethylene glycol), citrate ester-type plasticizers,triacetin, propylene glycol and glycerin. Such plasticizers can alsoinclude ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol,styrene glycol, diethylene glycol, triethylene glycol, tetraethyleneglycol and other poly(ethylene glycol) compounds, monopropylene glycolmonoisopropyl ether, propylene glycol monoethyl ether, ethylene glycolmonoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate,ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate,acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate,tributyl citrate and allyl glycolate. All such plasticizers arecommercially available from sources such as Aldrich or Sigma ChemicalCo. It is also contemplated and within the scope of the invention, thata combination of plasticizers may be used in the present formulation.The PEG based plasticizers are available commercially or can be made bya variety of methods, such as disclosed in Poly(ethylene glycol)Chemistry: Biotechnical and Biomedical Applications (J. M. Harris, Ed.;Plenum Press, NY) the disclosure of which is hereby incorporated byreference.

The multi-layered tablet of the invention can also include oils, forexample, fixed oils, such as peanut oil, sesame oil, cottonseed oil,corn oil and olive oil; fatty acids, such as oleic acid, stearic acidand isostearic acid; and fatty acid esters, such as ethyl oleate,isopropyl myristate, fatty acid glycerides and acetylated fatty acidglycerides. It can also be mixed with alcohols, such as ethanol,isopropanol, hexadecyl alcohol, glycerol and propylene glycol; withglycerol ketals, such as 2,2-dimethyl-1,3-dioxolane-4-methanol; withethers, such as poly(ethyleneglycol) 450, with petroleum hydrocarbons,such as mineral oil and petrolatum; with water, or with mixturesthereof; with or without the addition of a pharmaceutically suitablesurfactant, suspending agent or emulsifying agent.

Soaps and synthetic detergents may be employed as surfactants and asvehicles for detergent compositions. Suitable soaps include fatty acidalkali metal, ammonium, and triethanolamine salts. Suitable detergentsinclude cationic detergents, for example, dimethyl dialkyl ammoniumhalides, alkyl pyridinium halides, and alkylamine acetates; anionicdetergents, for example, alkyl, aryl and olefin sulfonates, alkyl,olefin, ether and monoglyceride sulfates, and sulfosuccinates; nonionicdetergents, for example, fatty amine oxides, fatty acid alkanolamides,and poly(oxyethylene)-block-poly(oxypropylene) copolymers; andamphoteric detergents, for example, alkyl β-aminopropionates and2-alkylimidazoline quaternary ammonium salts; and mixtures thereof.

Various other components, not otherwise listed above, can be added tothe multi-layered tablet of the invention for optimization of a desiredactive agent release profile including, by way of example and withoutlimitation, glycerolmonostearate, nylon, cellulose acetate butyrate, d,1-poly(lactic acid), 1,6-hexanediamine, diethylenetriamine, starches,derivatized starches, acetylated monoglycerides, gelatin coacervates,poly (styrene-maleic acid) copolymer, glycowax, castor wax, stearylalcohol, glycerol palmitostearate, poly(ethylene), poly(vinyl acetate),poly(vinyl chloride), 1,3-butylene-glycoldimethacrylate,ethyleneglycol-dimethacrylate and methacrylate hydrogels.

It should be understood, that compounds used in the art ofpharmaceutical formulation generally serve a variety of functions orpurposes. Thus, if a compound named herein is mentioned only once or isused to define more than one term herein, its purpose or function shouldnot be construed as being limited solely to that named purpose(s) orfunction(s).

The dosage forms of the invention can include surface markings,cuttings, grooves, letters and/or numerals for the purposes ofdecoration, identification and/or other purposes.

The multi-layered tablet can include a finish coat as is commonly donein the art to provide the desired shine, color, taste or other aestheticcharacteristics. Materials suitable for preparing the finish coat arewell known in the art and found in the disclosures of many of thereferences cited and incorporated by reference herein.

Materials which are suitable for use in an immediate release or rapidrelease coating include, by way of example and without limitation, watersoluble polysaccharide gums such as carrageenan, fucoidan, gum ghatti,tragacanth, arabinogalactan, pectin, and xanthan; water-soluble salts ofpolysaccharide gums such as sodium alginate, sodium tragacanthin, andsodium gum ghattate; water-soluble hydroxyalkylcellulose wherein thealkyl member is straight or branched of 1 to 7 carbons such ashydroxymethylcellulose, hydroxyethylcellulose, andhydroxypropylcellulose; synthetic water-soluble and low molecular weightcellulose-based lamina formers such as methyl cellulose and itshydroxyalkyl methylcellulose cellulose derivatives such as a memberselected from the group consisting of hydroxyethyl methylcellulose,hydroxypropyl methylcellulose, and hydroxybutyl methylcellulose;croscarmellose sodium; other cellulose polymers such as sodiumcarboxymethylcellulose; and other materials known to those of ordinaryskill in the art. Other materials include poly(vinylpyrrolidone),polyvinylalcohol, polyethylene oxide, a blend of gelatin andpolyvinyl-pyrrolidone, gelatin, glucose, saccharides, povidone,copovidone, poly(vinylpyrrolidone)-poly(vinyl acetate) copolymer. Theartisan of ordinary skill will recognize that the above-noted materialsinclude film-forming polymers that are not release rate controllingmaterials even though they may include the same chemical functionalitythereof. This is because film-forming polymers that do not controlrelease rate generally have lower molecular weight than otherwisesimilar film-forming polymers having higher molecular weight.

The immediate release or rapid release coating can also include a watersoluble and/or erodible, inert and non-toxic material that is at leastpartially, and optionally substantially completely, soluble or erodiblein an environment of use. Exemplary materials are disclosed in U.S. Pat.No. 4,576,604 to Guittard et al. and U.S. Pat. No. 4,673,405 to Guittardet al., and U.S. Pat. No. 6,004,582 to Faour et al. and the textPharmaceutical Dosage Forms: Tablets Volume I, 2^(nd) Edition. (A.Lieberman. ed. 1989, Marcel Dekker, Inc.), the relevant disclosures ofwhich are hereby incorporated by reference.

A “gastro-resistant coating” or delayed release material (coating) usedin the multi-layered tablet of the invention will possess limitedsolubility or erodibility or be insoluble or non-erodible in a firstexternal fluid, while being soluble and/or erodible in a second externalfluid. For example, the delayed release material may be insoluble in thefluid of a first environment of use, such as gastric juices, acidicfluids, or polar liquids, and soluble or erodible in the fluid of asecond environment of use, such as intestinal juices, substantially pHneutral or basic fluids, or apolar liquids. A wide variety of otherpolymeric materials are known to possess these various solubilityproperties and can be used. Such other polymeric materials include, byway of example and without limitation, cellulose acetate phthalate(CAP), cellulose acetate trimelletate (CAT), poly(vinylacetate)phthalate (PVAP), hydroxypropyl methylcellulose phthalate(HPMCP), poly(methacrylate ethylacrylate) (1:1) copolymer (MA-EA),poly(methacrylate methylmethacrylate) (1:1) copolymer (MA-MMA),poly(methacrylate methylmethacrylate) (1:2) copolymer, EUDRAGIT™ L-30-D(MA-EA, 1:1), EUDRAGIT™ L-100-55 (MA-EA, 1:1), hydroxypropylmethylcellulose acetate succinate (HPMCAS), COATERIC™ (PVAP), AQUATERIC™(CAP), AQOAT™ (HPMCAS) and combinations thereof.

An optional polymeric material for the delayed release material/coatingis a poly(vinylpyrrolidone)-vinyl acetate copolymer, such as thematerial supplied by BASF under its KOLLIDON VA64 trademark. This can bemixed with other excipients such as magnesium stearate, povidone, whichis supplied by BASF under its KOLLIDON K 30 trademark, and hydroxypropylmethylcellulose, which is supplied by Dow under its METHOCEL E-15trademark. The materials can be prepared in solutions having differentconcentrations of polymer according to the desired solution viscosity.For example, a 10% P/V aqueous solution of KOLLIDON™ K 30 has aviscosity of about 5.5-8.5 cps at 20° C., and a 2% P/V aqueous solutionof METHOCEL™ E-15 has a viscosity of about 13-18 cps at 20° C.

The delayed release composition can also comprise other materialssuitable which are substantially resistant to gastric juices and whichwill promote enteric release. These materials do not dissolve,disintegrate, or change their structure in the stomach and during theperiod of time that the dosage form resides in the stomach.Representative materials that keep their integrity in the stomach cancomprise a member selected from the group consisting of (a) keratin,keratin sandarac-tolu, salol (phenyl salicylate), salolbeta-naphthylbenzoate and acetotannin, salol with balsam of Peru, salolwith tolu, salol with gum mastic, salol and stearic acid, and salol andshellac; (b) a member selected from the group consisting of formalizedprotein, formalized gelatin, and formalized cross-linked gelatin andexchange resins; (c) a member selected from the group consisting ofmyristic acid-hydrogenated castor oil-cholesterol, stearic acid-muttontallow, stearic acid-balsam of tolu, and stearic acid-castor oil; (d) amember selected from the group consisting of shellac, ammoniatedshellac, ammoniated shellac-salol, shellac-wool fat, shellac-acetylalcohol, shellac-stearic acid-balsam of tolu, and shellac n-butylstearate; (e) a member selected from the group consisting of abieticacid, methyl abictate, benzoin, balsam of tolu, sandarac, mastic withtolu, and mastic with tolu, and mastic with acetyl alcohol; (f) acrylicresins represented by anionic polymers synthesized from methacrylateacid and methacrylic acid methyl ester, copolymeric acrylic resins ofmethacrylic and methacrylic acid and methacrylic acid alkyl esters,copolymers of alkacrylic acid and alkacrylic acid alkyl esters, acrylicresins such asdimethylaminoethylmethacrylate-butylmethacrylate-methylmethacrylatecopolymer of 150,000 molecular weight, methacrylicacid-methylmethacrylate 50:50 copolymer of 135,000 molecular weight,methacrylic acid-methylmethacrylate-30:70-copolymer of 135,000 mol. wt.,methacrylic acid-dimethylaminoethyl-methacrylate-ethylacrylate of750,000 mol. wt., methacrylic acid-methylmethacrylate-ethylacrylate of1,000,000 mol. wt., and ethylacrylate-methylmethacrylate-ethylacrylateof 550,000 mol. wt; and, (g) an enteric composition comprising a memberselected from the group consisting of cellulose acetyl phthalate,cellulose diacetyl phthalate, cellulose triacetyl phthalate, celluloseacetate phthalate, hydroxypropyl methylcellulose phthalate, sodiumcellulose acetate phthalate, cellulose ester phthalate, cellulose etherphthalate, methylcellulose phthalate, cellulose ester-ether phthalate,hydroxypropyl cellulose phthalate, alkali salts of cellulose acetatephthalate, alkaline earth salts of cellulose acetate phthalate, calciumsalt of cellulose acetate phthalate, ammonium salt of hydroxypropylmethylcellulose phthalate, cellulose acetate hexahydrophthalate,hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetatephthalate (such as SURETERIC™ of Colorcon), diethyl phthalate, dibutylphthalate, dialkyl phthalate wherein the alkyl comprises from 1 to 7straight and branched alkyl groups, aryl phthalates, and other materialsknown to one or ordinary skill in the art.

By “release rate-controlling material” or “release rate modifier” ismeant a compound or combination of compounds that regulate or controlthe release of active agent from an extended release composition orlayer. The release rate-controlling material can be included within thematrix of an extended release composition and/or it can be included in afilm (coating) surrounding an extended release composition. For example,an extended release composition or layer can comprise a releaserate-controlling film and/or an embedded release rate-controllingmaterial within its matrix. The release rate-controlling material willassist in providing an extended release of the therapeutic agent and cancooperate with other components in the formulation to provide either adelayed, sustained, timed, pH dependent, targeted, or further controlleddelivery of the therapeutic agent. It will be understood that some ofthe binders mentioned herein can also be considered release ratemodifiers. Exemplary compounds suitable for use as a releaserate-controlling material include, without limitation, HPMC(hydroxypropyl methylcellulose), HPC (hydroxypropylcellulose), PEO(poly(ethylene oxide)), cellulose acetate butyrate, cellulose acetatepropionate, cellulose propionate, carrageenan, cellulose acetate,cellulose nitrate, methylcellulose, hydroxyethyl cellulose,ethylcellulose, polyvinyl acetate, latex dispersions, acacia,tragacanth, guar gum, gelatin, wax, and combinations thereof.

Other suitable polymers are well-known excipients commonly used in thefield of pharmaceutical formulations and are included in, for example,Remington's Pharmaceutical Sciences, 18th Edition, Alfonso R. Gennaro(editor), Mack Publishing Company, Easton, Pa., 1990, pp. 291-294;Alfred Martin, James Swarbrick and Arthur Commarata, Physical Pharmacy.Physical Chemical Principles in Pharmaceutical Sciences, 3rd edition(Lea & Febinger, Philadelphia, Pa., 1983, pp. 592-638); A. T. Florenceand D. Altwood, (Physicochemical Principles of Pharmacy, 2nd Edition,MacMillan Press, London, 1988, pp. 281-334. The entire disclosures ofthe references cited herein are hereby incorporated by references. Stillother suitable polymers include water-soluble natural polymers,water-soluble semi-synthetic polymers (such as the water-solublederivatives of cellulose) and water-soluble synthetic polymers. Thenatural polymers include polysaccharides such as inulin, pectin, alginderivatives (e.g. sodium alginate) and agar, and polypeptides such ascasein and gelatin. The semi-synthetic polymers include cellulosederivatives such as methylcellulose, hydroxyethylcellulose,hydroxypropyl cellulose, their mixed ethers such as hydroxypropylmethylcellulose and other mixed ethers such as hydroxyethylethylcellulose and hydroxypropyl ethylcellulose, hydroxypropylmethylcellulose phthalate and carboxymethylcellulose and its salts,especially sodium carboxymethylcellulose. The synthetic polymers includepolyoxyethylene derivatives (polyethylene glycols) and polyvinylderivatives (polyvinyl alcohol, polyvinylpyrrolidone and polystyrenesulfonate) and various copolymers of acrylic acid (e.g. carbomer). Othernatural, semi-synthetic and synthetic polymers not named here which meetthe criteria of water solubility, pharmaceutical acceptability andpharmacological inactivity are likewise considered to be within theambit of the present invention.

Solutes can be added to the tablet. These solutes can aid in either thesuspension or dissolution of drug. Exemplary solutes include organic andinorganic compounds such as salts, acids, bases, chelating agents,sodium chloride, lithium chloride, magnesium chloride, magnesiumsulfate, lithium sulfate, potassium chloride, sodium sulfite, calciumbicarbonate, sodium sulfate, calcium sulfate, calcium lactate,d-mannitol, urea, tartaric acid, raffinose, sucrose, alpha-d-lactosemonohydrate, glucose, combinations thereof and other similar orequivalent materials which are widely known in the art.

In standard dissolution assays, the values can vary depending upon theconditions employed. Moreover, the values may have an absolute standarddeviation (STD) of ±10%, ±5% or ±3% at each given time point.

Amantadine can be administered to late-stage Parkinsonian patients asadjunct (add-on or combination) therapy to levodopa for treatingdyskinesias. For example, PCT International Publication No. WO04/087116to Vergez et al. discloses a phase II, controlled study in adouble-blind setting carried out to evaluate the impact of thecombination of amantadine and citalopram in the UPDRS score of patientssuffering from motor fluctuations. The study showed clear evidences thatamantadine on top of levodopa treatment produced a significantimprovement in all of the motor fluctuation-related scores (UPDRS andAIMS) in fluctuating patients.

Example 1 discloses an exemplary multi-layered tablet comprising anosmotic core that provides amantadine ER, and an external IR or RRlevodopa/carbidopa-containing layer and an external ERlevodopa-containing layer in stacked arrangement with respect to and onopposite sides of the osmotic core.

FIGS. 5, 6, and 7 depict the release profile for formulations preparedas disclosed in Example 1. The in vitro testing was performed with USPType II dissolution apparatus (paddles), in 900 ml of HCl 0.1Nmaintained at a temperature of 37±0.5° C. The samples were tested byhigh pressure liquid chromatography. The amantadine release profile ofthe multi-layered tablets of Example 1 is described as follows anddisclosed in FIG. 5. The time is measured as from the instant that thetablet is initially placed in an aqueous environment.

Average Time (hrs) Released (%) SD Min Max 0 0 0 0 0 1 7 7.5 0 20 2.5 359.0 16 50 4 62 10.2 43 78 6 80 8.2 56 94 8 86 5.6 70 101 10 89 4.2 75102

The levodopa release profile of the multi-layered tablets of Example 1is disclosed in FIG. 6 and described as follows. The time is measured asfrom the instant that the tablet is initially placed in an aqueousenvironment.

Time (hrs) Average SD Min Max 0 0 0 0 0 0.5 52 10.0 30 65 1 65 6.0 44 772 80 4.0 55 88 3 87 5.5 65 102 4 95 3.5 85 101

The carbidopa release profile of the multi-layered tablets of Example 1is disclosed in FIG. 7 and described as follows. The time is measured asfrom the instant that the tablet is initially placed in an aqueousenvironment.

Average Time (min) Released (%) SD Min Max 0 0 0 0 0 10 40 5.9 20 55 2070 7.4 50 89 30 90 6.6 70 98 45 99 4.8 85 103

Example 2 discloses an exemplary multi-layered tablet comprising agastro-resistant coated core that provides a delayed and extendedrelease of levodopa, and an external IR or RRlevodopa/carbidopa-containing layer and an external ERamantadine-containing layer in stacked arrangement with respect to andon opposite sides of the gastro-resistant coated core.

FIGS. 8, 9, and 10 depict the release profile for formulations preparedas disclosed in Example 2. The in vitro testing is performed with USPType II dissolution apparatus (paddles), first in 700 ml of HCl 0.1Nmaintained at a temperature of 37±0.5° C., during 1 hour, and then in900 ml phosphate buffer pH 6 with 0.5-1% tween 80 or sodium laurylsulfate. The samples were tested by high pressure liquid chromatography.The amantadine release profile of the multi-layered tablets of Example 2is described as follows and disclosed in FIG. 8. The time is measured asfrom the instant that the tablet is initially placed in an aqueousenvironment.

Average Time (hrs) Released (%) SD Min Max 0 0 0 0 0 1 18 6.3 5 35 2 355.7 15 58 4 62 4.7 40 83 6 81 6.2 62 96 8 86 7.3 70 101

The levodopa release profile of the multi-layered tablets of Example 2is described as follows and disclosed in FIG. 9. The time is measured asfrom the instant that the tablet is initially placed in an aqueousenvironment.

Average Time (hrs) Released (%) SD Min Max 0 0 0 0 0 0.5 20 5.6 5 35 152 7.3 47 57 1.5 65 6.4 53 75 2 70 7.2 60 88 3 86 7.5 70 102 4 95 4.6 75101

The carbidopa release profile of the multi-layered tablets of Example 2is described as follows and disclosed in FIG. 10. The time is measuredas from the instant that the tablet is initially placed in an aqueousenvironment.

Average Time (min) Released (%) SD Min Max 0 0 0 0 0 10 45 4.9 22 65 2073 6.8 48 92 30 91 8.7 68 99 45 98 5.4 80 101

Example 7 discloses an exemplary multi-layered tablet comprising amatrix core that provides amantadine ER, and an external IR or RRlevodopa/carbidopa-containing layer and an external ERlevodopa-containing layer in stacked arrangement with respect to and onopposite sides of the matrix core.

FIGS. 11, 12, and 13, depict the release profile for formulationsprepared as disclosed in Example 7. The in vitro testing is performedwith USP Type II dissolution apparatus (paddles), in 900 ml of HCl 0.1Nat 50 rpm maintained at a temperature of 37±0.5° C. The amantadinerelease profile of the multi-layered tablets of Example 7 is disclosedin FIG. 11 and described as follows. The time is measured as from theinstant that the tablet is initially placed in an aqueous environment.

Average Time (hrs) Released (%) SD Min Max 0 0 0 0 0 2 36 5.0 15 55 4 674.6 40 82 6 81 2.3 56 94 8 87 4.7 73 101

The levodopa release profile of the multi-layered tablets of Example 7is disclosed in FIG. 12 and described as follows. The time is measuredas from the instant that the tablet is initially placed in an aqueousenvironment.

Average Time (hrs) Released (%) SD Min Max 0 0 0 0 0 0.5 51 12.5 31 66 166 7.9 43 75 2 81 6.6 56 89 4 94 6.4 85 102

The carbidopa release profile of the multi-layered tablets of Example 7is disclosed in FIG. 13 and described as follows. The time is measuredas from the instant that the tablet is initially placed in an aqueousenvironment.

Average Time (min) Released (%) SD Min Max 0 0 0 0 0 10 41 6.4 21 56 2072 8.5 49 88 30 92 7.4 71 97 45 98 7.1 86 101

The medications with the most evidence of efficacy in generalizedanxiety disorder (GAD) are the benzodiazepines, including a newlong-acting formulation of alprazolam. These drugs have a low incidenceof side effects but may cause physical dependence, withdrawal, andsedation. Antidepressants are also efficacious in GAD but act lessquickly than benzodiazepines (Rickels et al, J Clin Psychiatry. 2002; 63Suppl 14:9-16). Combining venlafaxine and alprazolam may lead to anincrease in improvement in patients not responding to one treatmentapproach alone; and adding ondensetron to the combination may help toavoid discontinuation of treatment do to nausea commonly caused byvenlafaxine.

Example 3 discloses a multi-layered tablet comprising an osmotic corethat provides venlafaxine CR, and an external IR or RRondensetron-containing layer and an external ER alprazolam-containinglayer in stacked arrangement with respect to and on opposite sides ofthe osmotic core.

FIGS. 14, 15, and 16 depict the release profile for formulationsprepared as disclosed in Example 3. The in vitro testing is performedwith USP Type II dissolution apparatus (paddles), in 900 ml of HCl 0.1Nwith 0.1% tween, maintained at a temperature of 37±0.5° C. Thevenlafaxine release profile of the multi-layered tablets of Example 3 isdisclosed in FIG. 14 and described as follows. The time is measured asfrom the instant that the tablet is initially placed in an aqueousenvironment.

Average Time (hrs) Released (%) SD Min Max 0 0 0 0 0 2 18 15.9 6 30 4 408.6 15 65 8 59 11.5 30 88 12 73 4.9 50 95 20 87 6.5 70 100 24 89 6.4 78101

The ondensetron release profile of the multi-layered tablets of Example3 is disclosed in FIG. 15 and described as follows. The time is measuredas from the instant that the tablet is initially placed in an aqueousenvironment.

Average Time (min) Released (%) SD Min Max 0 0 0 0 0 10 45 4.9 23 60 2072 6.8 47 91 30 85 8.7 57 98 45 99 5.4 70 101

The alprazolam release profile of the multi-layered tablets of Example 3is disclosed in FIG. 16 and described as follows. The time is measuredas from the instant that the tablet is initially placed in an aqueousenvironment.

Average Time (hrs) Released (%) SD Min Max 0 0 0 0 0 2 18 6.3 5 35 4 395.7 15 68 8 68 4.7 40 95 12 85 6.2 62 96

Example 8 discloses a multi-layered tablet comprising a capsulecontaining venlafaxine CR micro-osmotic tablets, and an external IR orRR ondensetron-containing layer and an external ER alprazolam-containinglayer in stacked arrangement with respect to and on opposite sides ofthe capsule.

FIGS. 17, 18, and 19 depict the release profile for formulationsprepared as disclosed in Example 8. The in vitro testing is performedwith USP Type II dissolution apparatus (paddles), in 900 ml of HCl 0.1Nwith 0.1% tween at 50 rpm maintained at a temperature of 37±0.5° C. Thevenlafaxine release profile of the multi-layered tablets of Example 8 isdisclosed in FIG. 17 and described as follows. The time is measured asfrom the instant that the tablet is initially placed in an aqueousenvironment.

Average Time (hrs) Released (%) SD Min Max 0 0 0 0 0 4 40 8.7 15 68 8 5911.5 30 87 15 78 10.4 57 97 20 87 8.9 70 100 24 89 7.8 75 101

The ondensetron release profile of the multi-layered tablets of Example8 is disclosed in FIG. 18 and described as follows. The time is measuredas from the instant that the tablet is initially placed in an aqueousenvironment.

Average Time (min) Released (%) SD Min Max 0 0 0 0 0 10 46 5.6 22 64 2071 6.7 42 92 30 86 8.4 58 97 45 97 5.1 72 102

The alprazolam release profile of the multi-layered tablets of Example 8is disclosed in FIG. 19 and described as follows. The time is measuredas from the instant that the tablet is initially placed in an aqueousenvironment.

Time Average (hrs) Released (%) SD Min Max 0 0 0 0 0 2 17 5.8 6 36 4 396.7 16 67 8 67 6.4 39 95 12 86 2.3 61 99

Coadministration of levodopa and carbidopa can be used for treatingParkinson's disease. Examples of additional active agents that mayfunction to augment or improve the treatment or conditions associatedwith Parkinson's disease include selegiline, COMT inhibitors such asentacapone or tolcapone, and dopamine agonists such as bromocriptine,ropinirole, pergolide, rotigotine, or pramipexole, and stomach motilitymodulators such as mosapride or domperidone. These active agents can beused alone or in combinations of two, three, four or more active agents.

Example 4 discloses a multi-layered tablet comprising an osmotic corethat provides ropinirole CR, and an external IR or RRlevodopa/carbidopa-containing layer and an external ERlevodopa-containing layer in stacked arrangement with respect to and onopposite sides of the osmotic core.

FIGS. 20, 21, and 22 depict the release profile for formulationsprepared as disclosed in Example 4. The in vitro testing is performedwith USP Type II dissolution apparatus (paddles), in 900 ml of HCl 0.1Nat 50 rpm maintained at a temperature of 37±0.5° C. The ropinirolerelease profile of the multi-layered tablets of Example 4 is disclosedin FIG. 20 and described as follows. The time is measured as from theinstant that the tablet is initially placed in an aqueous environment.

Time Average (hrs) Released (%) SD Min Max 0 0 0 0 0 1 7 7.5 0 20 2.5 359.0 16 50 4 62 10.2 43 78 6 80 8.2 56 94 8 86 5.6 70 101 12 89 4.2 75102

The levodopa release profile of the multi-layered tablets of Example 4is disclosed in FIG. 21 and described as follows. The time is measuredas from the instant that the tablet is initially placed in an aqueousenvironment.

Time Average (hrs) Released (%) SD Min Max 0 0 0 0 0 0.5 53 11.0 30 64 164 6.5 45 78 2 78 4.6 54 89 3 88 6.0 66 101 4 94 4.5 82 102

The carbidopa release profile of the multi-layered tablets of Example 4is disclosed in FIG. 22 and described as follows. The time is measuredas from the instant that the tablet is initially placed in an aqueousenvironment.

Time Average (min) Released (%) SD Min Max 0 0 0 0 0 10 41 5.8 19 56 2072 7.3 52 88 30 92 6.0 69 99 45 98 8.0 84 102

The combination of an atypical antipsychotic, with a serotonin reuptakeinhibitor for treating psychosis with major depressive disorder, mayhelp to find greater relief than using only an atypical antipsychoticagent. Combining venlafaxine and quetiapene may lead to an increase inimprovement in patients not responding to one treatment approach alone;and adding ondensetron to the combination may help to avoiddiscontinuation of treatment do to nausea commonly caused byvenlafaxine.

Example 5 discloses a multi-layered tablet comprising an osmotic corethat provides venlafaxine CR, and an external IR or RRondensetron-containing layer and an external ER quetiapene-containinglayer in stacked arrangement with respect to and on opposite sides ofthe osmotic core.

FIGS. 23, 24, and 25 depict the release profile for formulationsprepared as disclosed in Example 5. The in vitro testing is performedwith USP Type II dissolution apparatus (paddles), in 900 ml of HCl 0.1Nat 50 rpm maintained at a temperature of 37±0.5° C. The venlafaxinerelease profile of the multi-layered tablets of Example 5 is disclosedin FIG. 23 and described as follows. The time is measured as from theinstant that the tablet is initially placed in an aqueous environment.

Time Average (hrs) Released (%) SD Min Max 0 0 0 0 0 2 17 16.9 7 32 4 399.4 14 67 8 61 11.5 31 89 12 72 5.5 48 94 20 87 6.4 69 100 24 91 5.8 77101

The ondensetron release profile of the multi-layered tablets of Example5 is disclosed in FIG. 24 and described as follows. The time is measuredas from the instant that the tablet is initially placed in an aqueousenvironment.

Average Time (min) Released (%) SD Min Max 0 0 0 0 0 10 46 4.7 22 61 2074 7.8 47 91 30 85 7.9 56 98 45 98 8.2 71 102

The quetiapene release profile of the multi-layered tablets of Example 5is disclosed in FIG. 25 and described as follows. The time is measuredas from the instant that the tablet is initially placed in an aqueousenvironment.

Average Time (hrs) Released (%) SD Min Max 0 0 0 0 0 2 20 6.4 10 40 4 446.2 22 69 8 70 5.7 50 90 12 85 6.8 65 101

Quetiapene is use for the treatment of acute manic episodes associatedwith bipolar I disorder, as either monotherapy or adjunct therapy to themood stabilizers lithium or divalproex. Combining quetiapene and both,lithium and divalproex, may provide a more effective approach for thetreatment of acute manic episodes.

Example 6 discloses a multi-layered tablet comprising an osmotic corethat provides lithium ER, and an external IR or RR quetiapene-containinglayer and an external ER divalproex sodium-containing layer in stackedarrangement with respect to and on opposite sides of the osmotic core.

FIGS. 26, 27, and 28 depict the release profile for formulationsprepared as disclosed in Example 6. The in vitro testing is performedwith USP Type II dissolution apparatus (paddles), in 900 ml of HCl 0.1Nat 50 rpm maintained at a temperature of 37±0.5° C. The lithium releaseprofile of the multi-layered tablets of Example 6 is disclosed in FIG.26 and described as follows. The time is measured as from the instantthat the tablet is initially placed in an aqueous environment.

Average Time (hrs) Released (%) SD Min Max 0 0 0 0 0 2 35 16.9 15 68 468 9.4 45 87 8 91 5.8 73 101

The quetiapene release profile of the multi-layered tablets of Example 6is disclosed in FIG. 27 and described as follows. The time is measuredas from the instant that the tablet is initially placed in an aqueousenvironment.

Average Time (min) Released (%) SD Min Max 0 0 0 0 0 10 37 5.4 21 57 2065 8.6 43 87 30 82 6.4 54 99 45 95 6.7 70 104

The divalproex sodium release profile of the multi-layered tablets ofExample 6 is disclosed in FIG. 28 and described as follows. The time ismeasured as from the instant that the tablet is initially placed in anaqueous environment.

Average Time (hrs) Released (%) SD Min Max 0 0 0 0 0 2 21 7.4 10 43 4 475.6 27 67 8 75 5.9 50 90 12 81 4.8 64 100

Examples 9 discloses a multi-layered tablet comprising agastro-resistant coated core that provides a delayed and extendedrelease of levodopa, and an external IR or RR of carbidopa-containinglayer, and an external ER entacapone-containing layer in stackedarrangement with respect to and on opposite sides of thegastro-resistant coated core.

FIGS. 29, 30, and 31 depict the release profile for formulationsprepared as disclosed in Example 9. The entacapone release profile ofthe multi-layered tablets of Example 9 is described as follows anddisclosed in FIG. 29. The in vitro testing is performed with USP TypeIII dissolution apparatus, in 250 ml of USP phosphate buffer pH 6.8 with1% tween. The samples were tested by high pressure liquidchromatography. The time is measured as from the instant that the tabletis initially placed in an aqueous environment.

Average Time (hrs) Released (%) SD Min Max 0 0 0 0 0 1 37 7.8 20 53 2 706.9 48 85 3 88 6.8 65 98 4 95 7.8 78 100

The levodopa release profile of the multi-layered tablets of Example 9is described as follows and disclosed in FIG. 30. The in vitro testingis performed with USP Type II dissolution apparatus (paddles), first in900 ml of HCl 0.1N maintained at a temperature of 37±0.5° C., during 1hour, and then the medium is adjusted to pH 6 with 1% tween. The sampleswere tested by high pressure liquid chromatography. The time is measuredas from the instant that the tablet is initially placed in an aqueousenvironment.

Average Time (hrs) Released (%) SD Min Max 0 0 0 0 0 0.5 0 15.0 0 2 1 018.0 0 4 1.5 50 15.4 30 75 2.5 87 7.5 65 101 4 95 5.3 75 102

The carbidopa release profile of the multi-layered tablets of Example 9is described as follows and disclosed in FIG. 31. The time is measuredas from the instant that the tablet is initially placed in an aqueousenvironment.

Average Time (min) Released (%) SD Min Max 0 0 0 0 0 10 41 5.4 21 54 2071 6.5 49 90 30 89 6.9 69 99 45 98 5.4 84 102

Example 10 discloses a multi-layered tablet comprising agastro-resistant coated core that provides a delayed and extendedrelease of levodopa, and an external IR or RRlevodopa/carbidopa-containing layer and an external ERentacapone-containing layer in stacked arrangement with respect to andon opposite sides of the gastro-resistant coated core.

FIGS. 32, 33, and 34 depict the release profile for formulationsprepared as disclosed in Example 10. The entacapone release profile ofthe multi-layered tablets of Example 10 is described as follows anddisclosed in FIG. 32. The in vitro testing is performed with USP TypeIII dissolution apparatus, in 250 ml of USP phosphate buffer pH 6.8 with1% tween. The samples were tested by high pressure liquidchromatography. The time is measured as from the instant that the tabletis initially placed in an aqueous environment.

Average Time (hrs) Released (%) SD Min Max 0 0 0 0 0 1 38 8.4 19 54 2 716.5 49 87 3 87 5.7 68 101 4 96 8.5 77 102

The levodopa release profile of the multi-layered tablets of Example 10is described as follows and disclosed in FIG. 33. The in vitro testingis performed with USP Type II dissolution apparatus (paddles), first in900 ml of HCl 0.1N maintained at a temperature of 37±0.5° C., during 1hour, and then the medium is adjusted to pH 6 with 1% tween. The sampleswere tested by high pressure liquid chromatography. The time is measuredas from the instant that the tablet is initially placed in an aqueousenvironment.

Average Time (hrs) Released (%) SD Min Max 0 0 0 0 0 0.5 23 6.5 9 38 151 7.2 44 56 1.5 66 6.6 54 76 2 71 7.1 61 88 3 87 7.4 71 101 4 96 5.4 74101

The carbidopa release profile of the multi-layered tablets of Example 10is described as follows and disclosed in FIG. 34. The time is measuredas from the instant that the tablet is initially placed in an aqueousenvironment.

Average Time (min) Released (%) SD Min Max 0 0 0 0 0 10 44 4.2 21 66 2074 6.7 47 93 30 90 8.9 69 97 45 97 5.5 81 101

Naproxen is an arylacetic acid with analgesic and antipyreticproperties, member of the group of nonsteroidal anti-inflammatory drugs(NSAIDs). The mechanism of action is related to prostaglandin synthetaseinhibition. Ergotamine is an alpha adrenergic blocking agent with adirect stimulating effect on the smooth muscle of peripheral and cranialblood vessels and produces depression of central vasomotor centers.Domperidone is a dopamine-receptor blocking agent that does not crossthe blood-brain barrier and its action in the chemo-emetic trigger zoneproduces an anti-emetic effect. The combination of naproxen, ergotamineand domperidone would provide a symptomatic treatment for the acutemigraine attack, based on a consistent dose of a pain reliever, such asnaproxen, that will be enhance by the vasoconstrictor properties of anergot alkaloid, such as ergotamine. The co-administration of anantiemetic drug, such as domperidone, that also increases gastricmotility, is likely to facilitate the absorption of the other drugs and,at the same time, to diminish associated migraine symptoms, such asnausea and vomiting, helping to ameliorate the attack.

Example 11 discloses a multi-layered tablet comprising an osmotic corethat provides domperidone ER, and an external IR or RRergotamine-containing layer and an external ER naproxen-containing layerin stacked arrangement with respect to and on opposite sides of theosmotic core.

FIGS. 35, 36, and 37 depict the release profile for formulationsprepared as disclosed in Example 11. The in vitro testing is performedwith USP Type II dissolution apparatus (paddles), in 900 ml of HCl 0.1Nat 50 rpm maintained at a temperature of 37±0.5° C. The domperidonerelease profile of the multi-layered tablets of Example 11 is disclosedin FIG. 35 and described as follows. The time is measured as from theinstant that the tablet is initially placed in an aqueous environment.

Average Time (hrs) Released (%) SD Min Max 0 0 0 0 0 1 7 7.3 0 19 2.5 359.1 18 52 4 62 9.9 42 78 6 80 8.5 54 92 8 86 5.4 71 100 12 89 4.0 76 101

The ergotamine release profile of the multi-layered tablets of Example11 is disclosed in FIG. 36 and described as follows. The time ismeasured as from the instant that the tablet is initially placed in anaqueous environment.

Average Time (min) Released (%) SD Min Max 0 0 0 0 0 10 40 4.5 21 60 2073 7.6 47 90 30 85 7.8 56 97 45 99 8.0 70 102

The naproxen release profile of the multi-layered tablets of Example 11is disclosed in FIG. 37 and described as follows. The time is measuredas from the instant that the tablet is initially placed in an aqueousenvironment.

Average Time (hrs) Released (%) SD Min Max 0 0 0 0 0 2 20 7.0 11 43 4 465.4 26 65 8 77 5.8 49 91 12 82 4.5 64 99

The following examples should not be considered exhaustive, but merelyillustrative of only a few of the many embodiments contemplated by thepresent invention. The methods described herein can be followed toprepare tablets according to the invention.

EXAMPLE 1

The following procedure is used to prepare a multi-layered tabletcomprising an osmotic device (intermediate drug-containing composition)that provides amantadine ER, and an external IR or RRlevodopa/carbidopa-containing layer and an external ERlevodopa-containing layer in stacked arrangement with respect to and onopposite sides of the osmotic core. An exemplary formulation isdisclosed below.

Ingredients/functional category Amount (mg) Osmotic device CoreAmantadine HCl 160   Filler 1 10.0-50.0  Binder 5.0-15.0 Glidant0.15-3.0  Lubricant 0.5-5.0  Osmotic agent 0-75 Filler 2 5.0-30.0Semipermeable Membrane Cellulose ester 1   0-30.0 Cellulose ester 2  0-30.0 Plasticizer 0.3-1.5  Dry Coating Layer A (IR/RR) Levodopa 100.0Carbidopa  50.0 Filler 1 20.0-300.0 Filler 2 20.0-300.0 Binder 5.0-50.0Disintegrant 5.0-20.0 Glidant 0.2-5.0  Lubricant 1.0-5.0  Layer B (ER)Levodopa 100.0 ER Polymer 1.0-10.0 Filler 1 20.0-300.0 Filler 220.0-300.0 Plasticizer 10.0-50.0  Inorganic salt 1.0-30.0 Glidant0.2-5.0  Lubricant 1.0-5.0 

Amantadine hydrochloride, filler 1, filler 2, and a binder, are firstindividually screened to a uniform size using a Quadro Comil at lessthan 500 rpm, and then mixed with osmotic agent previously milled usinga Fitz Mill with a screen 0020-0069 at less than 8000 rpm, in a mixergranulator for up to 5 minutes to form a homogenous powder blend. Thegranulation process is initiated by the gradual addition of purifiedwater to the powder blend, with continuous mixing, to change theconsistency of the dry powder ingredients to granules. The wetgranulation is sieved through a Quadro Comil at a speed less than 500rpm, and then dried in a static bed at 50° C. for humidity reduction.Next, the dry granules are milled using a Quadro Comil with a screenR991μ at less than 2,000 rpm for size reduction. Then, a mixture of aglidant and a lubricant, previously sieved through a 60-mesh screen, isadded and mixed for about 5 minutes. The resulting mixture is compressedin a compressor with 7-10 mm diameter punches to form uncoated cores.

A semipermeable membrane composition is prepared as follows: celluloseester 1, cellulose ester 2, and a plasticizer of low molecular weightare blended in acetone and purified water. The blend is sprayed onto theuncoated cores to obtain coated cores. The semipermeable membrane weightrange is approximately between 8 and 20 mg. The coated cores are thenperforated with a laser equipment to form at least one passageway of0.2-0.8 mm of diameter.

The IR/RR composition (layer A) is prepared as follows: the levodopa,carbidopa, filler 1, filler 2, binder and half of the disintegrant arefirst individually screened in a rotary mill with a 991 μm screen, andthen mixed in a mixer granulator for up to 10 minutes to form ahomogenous powder blend. The granulation process is initiated by thegradual addition of purified water to the powder blend, with continuousmixing, to change the consistency of the dry powder ingredients togranules. The wet granulation is dried in a static bed at 50-70° C. orin a fluid bed at 40-60° C. for humidity reduction. Next, the drygranules are milled using a rotary mill with a 1575 μm screen at lessthan 1200 rpm for size reduction. Then, glidant, lubricant, and theother half of the disintegrant, previously sieved through a 30-meshscreen, are added and mixed for about 5 minutes to obtain the IR/RRcomposition.

The ER layer (layer B) composition is prepared as follows: the levodopaand ER polymer are first individually screened in a rotary mill with a991 μm screen, and then mixed with filler 1, filler 2 and inorganic saltpreviously milled using a hammer mill with a 0020 screen, in a mixergranulator for up to 10 minutes to form a homogenous powder blend. Thegranulation process is initiated by the gradual addition of purifiedwater to the powder blend, with continuous mixing, to change theconsistency of the dry powder ingredients to granules.

The wet granulation is dried in a static bed at 50-70° C. or in a fluidbed at 40-60° C. for humidity reduction. Next, the dry granules aremilled using a rotary mill with a 1575 μm screen at less than 1200 rpmfor size reduction. Then, the glidant, plasticizer and lubricant,previously sieved through a 30-mesh screen, are added and mixed forabout 5 minutes to obtain the ER layer composition.

The multi-layered tablets are manufactured as follows: the IR/RRcomposition is loaded into the first hopper (first filled position) ofthe tableting machine, the ER composition is loaded into the secondhopper (second filled position) of the tableting machine, and theosmotic cores are placed into the internal core dispenser. The die isfirst filled with 200-850 mg of IR/RR composition, and then the osmoticcore is dispensed onto the first composition. After that the die isfilled with 150-800 mg of ER composition and finally all the componentsare compressed to obtained the multi-layered tablets.

EXAMPLE 2

The following procedure is used to prepare a multi-layered tabletcomprising a gastro-resistant coated core (exemplary intermediatedrug-containing composition) that provides a delayed and extendedrelease of levodopa, and an external IR or RRlevodopa/carbidopa-containing layer and an external ERamantadine-containing layer in stacked arrangement with respect to andon opposite sides of the gastro-resistant coated core. An exemplaryformulation is disclosed below.

Ingredients/functional category Amount (mg) Gastro-resistant coated coreCore (ER) Levodopa 100.0 Filler  5.0-100.0 CR polymer 1.0-20.0 Glidant0.2-5.0  Lubricant 1.0-5.0  Enteric coating (DR) Enteric film polymer 5.0-200.0 Plasticizer (optional) 0.1-20.0 Plasticizer 0.3-1.5  DryCoating Layer A (IR/RR) Levodopa 100.0 Carbidopa  50.0 Filler 120.0-300.0 Filler 2 20.0-300.0 Binder 5.0-50.0 Disintegrant 5.0-20.0Glidant 0.2-5.0  Lubricant 1.0-5.0  Layer B (ER) Amantadine 160.0 CRPolymer 1.0-10.0 Filler 1 20.0-300.0 Filler 2 20.0-300.0 Plasticizer10.0-50.0  Inorganic salt 1.0-30.0 Glidant 0.2-5.0  Lubricant 1.0-5.0 

The ER core composition is prepared as follows: the levodopa and CRpolymer are first individually screened in a rotary mill with a 991 μmscreen, and then mixed with filler, in a mixer granulator for up to 10minutes to form a homogenous powder blend. The granulation process isinitiated by the gradual addition of purified water to the powder blend,with continuous mixing, to change the consistency of the dry powderingredients to granules. The wet granulation is dried in a static bed at50-70° C. or in a fluid bed at 40-60° C. for humidity reduction. Next,the dry granules are milled using a rotary mill with a 1575 μm screen atless than 1200 rpm for size reduction. Then, the glidant and thelubricant, previously sieved through a 30-mesh screen, are added andmixed for about 5 minutes. The final blend is tableted to provide thecores.

The enteric coating composition is prepared as follows: the enteric filmpolymer, and the plasticizer are blended in purified water to form apolymer suspension. This suspension is sprayed onto the cores in aperforated pan coater to obtain gastro-resistant coated cores.

The IR/RR composition (layer A) is prepared as follows: the levodopa,carbidopa, filler 1, filler 2, binder, and half of the disintegrant arefirst individually screened in a rotary mill with a 991 μm screen, andthen mixed in a mixer granulator for up to 10 minutes to form ahomogenous powder blend. The granulation process is initiated by thegradual addition of purified water to the powder blend, with continuousmixing, to change the consistency of the dry powder ingredients togranules. The wet granulation is dried in a static bed at 50-70° C. orin a fluid bed at 40-60° C. for humidity reduction. Next, the drygranules are milled using a rotary mill with a 1575 μm screen at lessthan 1200 rpm for size reduction. Then, the glidant, lubricant, and theother half of the disintegrant, previously sieved through a 30-meshscreen, are added and mixed for about 5 minutes to obtain the IR/RRcomposition.

The ER layer (layer B) composition is prepared as follows: amantadineand the CR polymer are first individually screened in a rotary mill witha 991 μm screen, and then mixed with filler 1, filler 2 and inorganicsalt previously milled using a hammer mill with a 0020 screen, in amixer granulator for up to 10 minutes to form a homogenous powder blend.The granulation process is initiated by the gradual addition of purifiedwater to the powder blend, with continuous mixing, to change theconsistency of the dry powder ingredients to granules. The wetgranulation is dried in a static bed at 50-70° C. or in a fluid bed at40-60° C. for humidity reduction. Next, the dry granules are milledusing a rotary mill with a 1575 μm screen at less than 1200 rpm for sizereduction. Then, the glidant, plasticizer, and lubricant, previouslysieved through a 30-mesh screen, are added and mixed for about 5 minutesto obtain the ER composition.

The multi-layered tablets are manufactured as follows: the IR/RRcomposition is loaded into the first hopper (first filled position) ofthe tableting machine, the ER composition is loaded into the secondhopper (second filled position) of the tableting machine, and the drygastro-resistant coated cores are placed into the internal coredispenser. The die is first filled with 200-830 mg of IR/RR composition,and then the gastro-resistant coated core is dispensed onto the firstcomposition. After that the die is filled with 200-860 mg of ERcomposition and finally all the components are compressed to obtainedthe multi-layered tablets.

EXAMPLE 3

The following procedure is used to prepare a multi-layered tabletcomprising an osmotic device that provides venlafaxine CR, and anexternal IR or RR ondensetron-containing layer and an external ERalprazolam-containing layer in stacked arrangement with respect to andon opposite sides of the osmotic core. An exemplary formulation isdisclosed below.

Ingredients/functional category Amount (mg) Osmotic device CoreVenlafaxine Hydrochloride 169.72  Filler 30.0-100.0 Osmotic salt10.0-80.0  Binder 10.0-30.0  Plasticizer 1 1.0-5.0  Glidant 2.0-10.0Plasticizer 2 20.0-50.0  Lubricant  2.0-15.00 Semipermeable MembraneCellulose ester  1.0-100.0 Plasticizer 2.0-10.0 Dry Coating Layer A(IR/RR) Ondansetron HCl•2H2O 5.0 Filler 1 50.0-200.0 Filler 2 50.0-200.0Binder 4.0-40.0 Disintegrant 3.0-20.0 Glidant 0.2-5.0  Lubricant1.0-5.0  Layer B (ER) Alprazolam 1.0 ER Polymer 1.0-10.0 Filler 150.0-200.0 Filler 2 50.0-200.0 Plasticizer 10.0-70.0  Inorganic Salt1.0-40.0 Glidant 0.2-5.0  Lubricant 1.0-10.0

Venlafaxine hydrochloride, the filler, and the binder, are firstindividually screened to a uniform size using a Quadro Comil at lessthan 1,000 rpm, and then mixed with the osmotic salt previously milledusing a Fitz Mill with a screen 0020-0069 at less than 8000 rpm, in amixer granulator for up to 25 minutes to form a homogenous powder blend.The granulation process is initiated by adding a solution containing aplasticizer of low molecular weight and a plasticizer of highermolecular weight in purified water for granules. The wet granulation issieved through a Quadro Comil at a speed less than 1000 rpm, and thendried in a static bed at 50° C. for humidity reduction. Next, the drygranules are milled using a Quadro Comil with a screen R991μ at lessthan 2,000 rpm for size reduction. Then, a mixture of the glidant andthe lubricant, previously sieved through a 100-mesh screen, is added andmixed for about 15 minutes. The resulting mixture is compressed in acompressor with 8.0 mm diameter punches to form uncoated cores.

A semipermeable membrane composition is prepared as follows: celluloseester, and the plasticizer of low molecular weight are blended in amixture of solvents. The blend is sprayed onto the uncoated cores toobtain coated cores. The coated cores are then perforated with a laserequipment to form at least one passageway of 0.2-0.8 mm of diameter.

The immediate or rapid release composition (layer A) is prepared asfollows: the ondensetron, filler 1, filler 2, binder and half of thedisintegrant are first individually screened in a rotary mill with a 991μm screen, and then mixed in a mixer granulator for up to 10 minutes toform a homogenous powder blend. The granulation process is initiated bythe gradual addition of purified water to the powder blend, withcontinuous mixing, to change the consistency of the dry powderingredients to granules. The wet granulation is dried in a static bed at50-70° C. or in a fluid bed at 40-60° C. for humidity reduction. Next,the dry granules are milled using a rotary mill with a 1575 μm screen atless than 1200 rpm for size reduction. Then, glidant, lubricant and theother half of the disintegrant, previously sieved through a 30-meshscreen, are added and mixed for about 5 minutes.

The extended release layer (layer B) composition is prepared as follows:alprazolam and ER polymer are first individually screened in a rotarymill with a 991 μm screen, and then mixed with filler 1, filler 2 andinorganic salt previously milled using a hammer mill with a 0020 screen,in a mixer granulator for up to 10 minutes to form a homogenous powderblend. The granulation process was initiated by the gradual addition ofpurified water to the powder blend, with continuous mixing, to changethe consistency of the dry powder ingredients to granules. The wetgranulation is dried in a static bed at 50-70° C. or in a fluid bed at40-60° C. for humidity reduction. Next, the dry granules are milledusing a rotary mill with a 1575 μm screen at less than 1200 rpm for sizereduction. Then, the glidant, plasticizer and lubricant, previouslysieved through a 30-mesh screen, are added and mixed for about 5minutes.

The multi-layered tablets are manufactured as follows: the IR/RRcomposition is loaded into the first hopper (first filled position) ofthe tableting machine, the ER composition is loaded into the secondhopper (second filled position) of the tableting machine, and theosmotic cores are placed into the internal core dispenser. The die isfirst filled with 100-500 mg of IR/RR composition, and then the osmoticcore is dispensed onto the first composition. After that the die isfilled with 100-540 mg of ER composition and finally all the componentsare compressed to obtained the multi-layered tablets.

EXAMPLE 4

The following procedure is used to prepare a multi-layered tabletcomprising an osmotic device that provides ropinirole CR, and anexternal IR or RR levodopa/carbidopa-containing layer and an external ERlevodopa-containing layer in stacked arrangement with respect to and onopposite sides of the osmotic core. An exemplary formulation isdisclosed below.

Ingredients/functional category Amount (mg) Osmotic device CoreRopinirole  3.0 Filler 1 10.0-50.0  Binder 5.0-15.0 Glidant 0.15-3.0 Lubricant 0.5-5.0  Osmotic agent 0-75 Filler 2 5.0-30.0 SemipermeableMembrane Cellulose ester 1   0-30.0 Cellulose ester 2   0-30.0Plasticizer 0.3-1.5  Dry Coating Layer A (IR/RR) Levodopa 100.0Carbidopa  50.0 Filler 1 20.0-300.0 Filler 2 20.0-300.0 Binder 5.0-50.0Disintegrant 5.0-20.0 Glidant 0.2-5.0  Lubricant 1.0-5.0  Layer B (ER)Levodopa 100.0 ER Polymer 1.0-10.0 Filler 1 20.0-300.0 Filler 220.0-300.0 Plasticizer 10.0-50.0  Inorganic salt 1.0-30.0 Glidant0.2-5.0  Lubricant 1.0-5.0 

Ropinirole, filler 1, filler 2, and the binder, are first individuallyscreened to a uniform size using a Quadro Comil at less than 500 rpm,and then mixed with the osmotic agent previously milled using a FitzMill with a screen 0020-0069 at less than 8000 rpm, in a mixergranulator for up to 5 minutes to form a homogenous powder blend. Thegranulation process is initiated by the gradual addition of purifiedwater to the powder blend, with continuous mixing, to change theconsistency of the dry powder ingredients to granules. The wetgranulation is sieved through a Quadro Comil at a speed less than 500rpm, and then dried in a static bed at 50° C. for humidity reduction.Next, the dry granules are milled using a Quadro Comil with a screenR991μ at less than 2,000 rpm for size reduction. Then, a mixture of theglidant and lubricant, previously sieved through a 60-mesh screen, isadded and mixed for about 5 minutes. The resulting mixture is compressedin a compressor with 7-10 mm diameter punches to form uncoated cores.

A semipermeable membrane composition is prepared as follows: celluloseester 1, cellulose ester 2, and the plasticizer of low molecular weightare blended in acetone and purified water. The blend is sprayed onto theuncoated cores to obtain coated cores. The semipermeable membrane weightrange is approximately between 8 and 20 mg. The membrane coating of eachcore is then perforated with laser equipment to form at least onepassageway of 0.2-0.8 mm through the semipermeable coat.

The immediate or rapid release composition (layer A) is prepared asfollows: the levodopa, carbidopa, filler 1, filler 2, the binder andhalf of the disintegrant are first individually screened in a rotarymill with a 991 μm screen, and then mixed in a mixer granulator for upto 10 minutes to form a homogenous powder blend. The granulation processis initiated by the gradual addition of purified water to the powderblend, with continuous mixing, to change the consistency of the drypowder ingredients to granules. The wet granulation is dried in a staticbed at 50-70° C. or in a fluid bed at 40-60° C. for humidity reduction.Next, the dry granules are milled using a rotary mill with a 1575 μmscreen at less than 1200 rpm for size reduction. Then, the glidant,lubricant and the other half of the disintegrant, previously sievedthrough a 30-mesh screen, are added and mixed for about 5 minutes.

The extended release layer (layer B) composition is prepared as follows:the levodopa and ER polymer are first individually screened in a rotarymill with a 991 μm screen, and then mixed with filler 1, filler 2, andthe inorganic salt previously milled using a hammer mill with a 0020screen, in a mixer granulator for up to 10 minutes to form a homogenouspowder blend. The granulation process is initiated by the gradualaddition of purified water to the powder blend, with continuous mixing,to change the consistency of the dry powder ingredients to granules. Thewet granulation is dried in a static bed at 50-70° C. or in a fluid bedat 40-60° C. for humidity reduction. Next, the dry granules are milledusing a rotary mill with a 1575 μm screen at less than 1200 rpm for sizereduction. Then, the glidant, plasticizer, and lubricant, previouslysieved through a 30-mesh screen, are added and mixed for about 5minutes.

The multi-layered tablets are manufactured as follows: the IR/RRcomposition is loaded into the first hopper (first filled position) ofthe tableting machine, the ER composition is loaded into the secondhopper (second filled position) of the tableting machine, and theosmotic cores are placed into the internal core dispenser. The die isfirst filled with 200-830 mg of IR/RR composition, and then the osmoticcore is dispensed onto the first composition. After that the die isfilled with 150-800 mg of ER composition and finally all the componentsare compressed to obtained the multi-layered tablets.

EXAMPLE 5

The following procedure is used to prepare a multi-layered tabletcomprising an osmotic device that provides venlafaxine CR, and anexternal IR or RR ondensetron-containing layer and an external ERquetiapene-containing layer in stacked arrangement with respect to andon opposite sides of the osmotic core. An exemplary formulation isdisclosed below.

Ingredients/functional category Amount (mg) Osmotic device CoreVenlafaxine Hydrochloride  169.72 Filler 30.0-100.0 Osmotic agent10.0-80.0  Binder 10.0-30.0  Plasticizer 1 1.0-5.0  Glidant 2.0-10.0Plasticizer 2 20.0-50.0  Lubricant  2.0-15.00 Semipermeable MembraneCellulose ester  1.0-100.0 Plasticizer 2.0-10.0 Dry Coating Layer A(IR/RR) Ondansetron HCl•2H2O  5.0 Filler 1 50.0-200.0 Filler 250.0-200.0 Binder 4.0-40.0 Disintegrant 3.0-20.0 Glidant 0.2-5.0 Lubricant 1.0-5.0  Layer B (ER) Quetiapine 100.0 ER Polymer 1.0-10.0Filler 1 20.0-300.0 Filler 2 20.0-300.0 Plasticizer 10.0-50.0  Inorganicsalt 1.0-30.0 Glidant 0.2-5.0  Lubricant 1.0-5.0 

Venlafaxine hydrochloride, a filler, and a binder, are firstindividually screened to a uniform size using a Quadro Comil at lessthan 1,000 rpm, and then mixed with an osmotic agent previously milledusing a Fitz Mill with a screen 0020-0069 at less than 8000 rpm, in amixer granulator for up to 25 minutes to form a homogenous powder blend.The granulation process is initiated by adding a solution containing aplasticizer of low molecular weight and a plasticizer of highermolecular weight in purified water for granules. The wet granulation issieved through a Quadro Comil at a speed less than 1000 rpm, and thendried in a static bed at 50° C. for humidity reduction. Next, the drygranules are milled using a Quadro Comil with a screen R991μ at lessthan 2,000 rpm for size reduction. Then, a mixture of a glidant and alubricant, previously sieved through a 100-mesh screen, is added andmixed for about 15 minutes. The resulting mixture is compressed in acompressor with 8.0 mm diameter punches to form uncoated cores.

A semipermeable membrane composition is prepared as follows: celluloseester, and a plasticizer of low molecular weight are blended in amixture of solvents. The blend is sprayed onto the uncoated cores toobtain coated cores. The coated cores are then perforated with a laserequipment to form at least one passageway of 0.2-0.8 mm of diameter.

The immediate or rapid release composition (layer A) is prepared asfollows: the ondensetron, filler 1, filler 2, the binder and half of thedisintegrant are first individually screened in a rotary mill with a 991μm screen, and then mixed in a mixer granulator for up to 10 minutes toform a homogenous powder blend. The granulation process is initiated bythe gradual addition of purified water to the powder blend, withcontinuous mixing, to change the consistency of the dry powderingredients to granules. The wet granulation is dried in a static bed at50-70° C. or in a fluid bed at 40-60° C. for humidity reduction. Next,the dry granules are milled using a rotary mill with a 1575 μm screen atless than 1200 rpm for size reduction. Then, the glidant, lubricant, andthe other half of the disintegrant, previously sieved through a 30-meshscreen, are added and mixed for about 5 minutes.

The extended release layer (layer B) composition is prepared as follows:quetiapene and the ER polymer are first individually screened in arotary mill with a 991 μm screen, and then mixed with filler 1, filler 2and the inorganic salt previously milled using a hammer mill with a 0020screen, in a mixer granulator for up to 10 minutes to form a homogenouspowder blend. The granulation process is initiated by the gradualaddition of purified water to the powder blend, with continuous mixing,to change the consistency of the dry powder ingredients to granules. Thewet granulation is dried in a static bed at 50-70° C. or in a fluid bedat 40-60° C. for humidity reduction. Next, the dry granules are milledusing a rotary mill with a 1575 μm screen at less than 1200 rpm for sizereduction. Then, the glidant, plasticizer, and lubricant, previouslysieved through a 30-mesh screen, are added and mixed for about 5minutes.

The multi-layered tablets are manufactured as follows: the IR/RRcomposition is loaded into the first hopper (first filled position) ofthe tableting machine, the ER composition is loaded into the secondhopper (second filled position) of the tableting machine, and theosmotic cores are placed into the internal core dispenser. The die isfirst filled with 100-500 mg of IR/RR composition, and then the osmoticcore is dispensed onto the first composition. After that the die isfilled with 150-800 mg of ER composition and finally all the componentsare compressed to obtained the multi-layered tablets.

EXAMPLE 6

The following procedure is used to prepare a multi-layered tabletcomprising an osmotic device that provides lithium ER, and an externalIR or RR quetiapene-containing layer and an external ER divalproexsodium-containing layer in stacked arrangement with respect to and onopposite sides of the osmotic core. An exemplary formulation isdisclosed below.

Ingredients/functional category Amount (mg) Osmotic device Core Lithium300   Filler 1 20-100 Binder 10-30  Glidant 0.2-5   Lubricant 1-7 Sodium Chloride  0-150 Filler 2 10-60  Semipermeable Membrane Celluloseester 1   0-30.0 Cellulose ester 2   0-30.0 Plasticizer 0.3-1.5  DryCoating Layer A (IR/RR) Quetiapine 100.0 Filler 1 20.0-300.0 Filler 220.0-300.0 Binder 5.0-50.0 Disintegrant 5.0-20.0 Glidant 0.2-5.0 Lubricant 1.0-5.0  Layer B (ER) Divalproex Na 250.0 ER Polymer 2.5-50.0Filler 1 50.0-200.0 Filler 2 50.0-200.0 Plasticizer 25.0-100.0 Inorganicsalt 2.5-50.0 Glidant 0.5-12.5 Lubricant 2.5-12.5

Lithium, filler 1, filler 2, and a binder, are first individuallyscreened to a uniform size using a Quadro Comil at less than 500 rpm,and then mixed with sodium chloride previously milled using a Fitz Millwith a screen 0020-0069 at less than 8000 rpm, in a mixer granulator forup to 5 minutes to form a homogenous powder blend. The granulationprocess is initiated by the gradual addition of purified water to thepowder blend, with continuous mixing, to change the consistency of thedry powder ingredients to granules. The wet granulation is sievedthrough a Quadro Comil at a speed less than 500 rpm, and then dried in astatic bed at 50° C. for humidity reduction. Next, the dry granules aremilled using a Quadro Comil with a screen R991μ at less than 2,000 rpmfor size reduction. Then, a mixture of the glidant and the lubricant,previously sieved through a 60-mesh screen, is added and mixed for about5 minutes. The resulting mixture is compressed in a compressor with 7-10mm diameter punches to form uncoated cores.

A semipermeable membrane composition is prepared as follows: celluloseester 1, cellulose ester 2, and the plasticizer of low molecular weightare blended in acetone and purified water. The blend is sprayed onto theuncoated cores to obtain coated cores. The semipermeable membrane weightrange is approximately between 8 and 20 mg. The membrane coating of eachcore is then perforated with laser equipment to form at least onepassageway of 0.2-0.8 mm through the semipermeable coat.

The immediate or rapid release composition (layer A) is prepared asfollows: the quetiapene, filler 1, filler 2, the binder, and half of thedisintegrant are first individually screened in a rotary mill with a 991μm screen, and then mixed in a mixer granulator for up to 10 minutes toform a homogenous powder blend. The granulation process is initiated bythe gradual addition of purified water to the powder blend, withcontinuous mixing, to change the consistency of the dry powderingredients to granules. The wet granulation is dried in a static bed at50-70° C. or in a fluid bed at 40-60° C. for humidity reduction. Next,the dry granules are milled using a rotary mill with a 1575 μm screen atless than 1200 rpm for size reduction. Then, the glidant, lubricant, andthe other half of the disintegrant, previously sieved through a 30-meshscreen, are added and mixed for about 5 minutes.

The extended release layer (layer B) composition is prepared as follows:the divalproex Na and ER polymer are first individually screened in arotary mill with a 991 μm screen, and then mixed with filler 1, filler2, and the inorganic salt previously milled using a hammer mill with a0020 screen, in a mixer granulator for up to 10 minutes to form ahomogenous powder blend. The granulation process is initiated by thegradual addition of purified water to the powder blend, with continuousmixing, to change the consistency of the dry powder ingredients togranules. The wet granulation is dried in a static bed at 50-70° C. orin a fluid bed at 40-60° C. for humidity reduction. Next, the drygranules are milled using a rotary mill with a 1575 μm screen at lessthan 1200 rpm for size reduction. Then, the glidant, plasticizer, andlubricant, previously sieved through a 30-mesh screen, are added andmixed for about 5 minutes.

The multi-layered tablets are manufactured as follows: the IR/RRcomposition is loaded into the first hopper (first filled position) ofthe tableting machine, the ER composition is loaded into the secondhopper (second filled position) of the tableting machine, and theosmotic cores are placed into the internal core dispenser. The die isfirst filled with 150-800 mg of IR/RR composition, and then the osmoticcore is dispensed onto the first composition. After that the die isfilled with 350-880 mg of ER composition and finally all the componentsare compressed to obtained the multi-layered tablets.

EXAMPLE 7

The following procedure is used to prepare a multi-layered tabletcomprising a matrix core (exemplary intermediate drug-containingcomposition) that provides amantadine ER, and an external IR or RRlevodopa/carbidopa-containing layer and an external ERlevodopa-containing layer in stacked arrangement with respect to and onopposite sides of the matrix core. An exemplary formulation is disclosedbelow.

Ingredients/functional category Amount (mg) Matrix Core Amantadine HCl160   Filler 50.0-150.0 CR Polymer 1.0-20.0 Glidant 0.2-1.0  Lubricant0.2-1.0  Hydrophilic agent 5.0-25.0 Dry Coating Layer A (IR/RR) Levodopa100.0 Carbidopa  50.0 Filler 30.0-150.0 Binder 5.0-25.0 Disintegrant5.0-15.0 Glidant 0.5-2.5  Lubricant 0.5-5.0  Layer B (ER) Levodopa 100.0ER Polymer 1.0-15.0 Filler 50.0-150.0 Plasticizer 5.0-40.0 Glidant0.1-5.0  Lubricant 0.5-5.0 

Amantadine hydrochloride, the filler, and the CR polymer are firstscreened in a high shear granulator for up to 6-8 minutes to form ahomogenous powder blend. The granulation process is initiated by thegradual addition of purified water to the powder blend, with continuousmixing, to change the consistency of the dry powder ingredients togranules. The wet granulation is sieved through a #10 mesh screen, andthen dried in a fluid bed at 50° C. during 30-40 minutes for humidityreduction. Next, the dry granules are milled using a conic mill with a040G screen for size reduction. Then, a mixture of the glidant,lubricant, previously sieved through a 60-mesh screen, and thehydrophilic agent are added and mixed for about 5 minutes. The resultingmixture is compressed in a rotary tablet press with 7-8 mm diameterpunches to form the matrix cores.

The IR/RR composition (layer A) is prepared as follows: the levodopa,carbidopa, filler, binder and half of the disintegrant are firstindividually screened in a rotary mill with a 991 μm screen, and thenmixed in a mixer granulator for up to 10 minutes to form a homogenouspowder blend. The granulation process is initiated by the gradualaddition of purified water to the powder blend, with continuous mixing,to change the consistency of the dry powder ingredients to granules. Thewet granulation is dried in a fluid bed at 40-60° C. for humidityreduction. Next, the dry granules are milled using a rotary mill with a1575 μm screen at less than 1200 rpm for size reduction. Then, glidant,lubricant, and the other half of the disintegrant, previously sievedthrough a 30-mesh screen, are added and mixed for about 5 minutes toobtain the IR/RR composition.

The ER layer (layer B) composition is prepared as follows: the levodopaand ER polymer are first individually screened in a rotary mill with a991 μm screen, and then mixed with the filler in a mixer granulator forup to 10 minutes to form a homogenous powder blend. The granulationprocess is initiated by the gradual addition of purified water to thepowder blend, with continuous mixing, to change the consistency of thedry powder ingredients to granules. The wet granulation is dried in astatic bed at 50-70° C. or in a fluid bed at 40-60° C. for humidityreduction. Next, the dry granules are milled using a rotary mill with a1575 μm screen at less than 1200 rpm for size reduction. Then, theglidant, plasticizer and lubricant, previously sieved through a 30-meshscreen, are added and mixed for about 5 minutes to obtain the ER layercomposition.

The multi-layered tablets are manufactured as follows: the ERcomposition is loaded into the first hopper (first filled position) ofthe tableting machine, the IR/RR composition is loaded into the secondhopper (second filled position) of the tableting machine, and the matrixcores are placed into the internal core dispenser. The die is firstfilled with 150-320 mg of ER composition, and then the matrix core isdispensed onto the first composition. After that the die is filled with190-350 mg of IR/RR composition, and finally all the components arecompressed to obtained the multi-layered tablets.

EXAMPLE 8

The following procedure is used to prepare a multi-layered tabletcomprising a capsule (exemplary intermediate drug-containingcomposition) containing venlafaxine CR micro-osmotic tablets, and anexternal IR or RR ondensetron-containing layer and an external ERalprazolam-containing layer in stacked arrangement with respect to andon opposite sides of the capsule. An exemplary formulation is disclosedbelow.

Ingredients/functional category Amount (mg) Hard gelatin capsule 7micro-osmotic tablets per capsule Micro-osmotic tablet Core VenlafaxineHydrochloride 24.25 Osmotic agent  3.0-14.0 Binder 1.5-5.0 Plasticizer0.7-1.4 Glidant 0.1-0.8 Lubricant 0.2-0.8 Membrane Cellulose ester4.0-9.0 Plasticizer 0.3-0.9 Dry Coating Layer A (IR/RR) OndansetronHCl•2H2O 5.0 Filler  50.0-200.0 Binder  5.0-30.0 Disintegrant  2.0-10.0Glidant 0.5-3.0 Lubricant 0.5-4.0 Layer B (ER) Alprazolam 1.0 ER Polymer 5.0-20.0 Filler 1  20.0-100.0 Filler 2  20.0-150.0 Plasticizer10.0-30.0 Inorganic Salt  2.0-20.0 Glidant 0.1-5.0 Lubricant 1.0-5.0

Venlafaxine hydrochloride, the osmotic agent, and the binder, are mixedin a mixer granulator to form a homogenous powder blend. The granulationprocess is initiated by adding a solution of plasticizer in purifiedwater to the powder blend. The wet granulation is then dried at 40-50°C. for 3 hours. Next, the dry granules are screened and then mixed withthe glidant and the lubricant, previously sieved through a 100-meshscreen. The resulting mixture is compressed in a compressor with 3.0-4.0mm diameter punches to obtain micro-tablets of 34-50 mg each.

A membrane composition is prepared as follows: cellulose ester, and theplasticizer are blended in a mixture of solvents. The blend is sprayedonto the micro-tablets to obtain the micro-osmotic tablets. Hard gelatincapsules are filled with 7 micro-osmotic tablets per capsule.

The immediate or rapid release composition (layer A) is prepared asfollows: the ondensetron, the filler, the binder, and half of thedisintegrant are first individually screened in a rotary mill with a 991μm screen, and then mixed in a mixer granulator for up to 10 minutes toform a homogenous powder blend. The granulation process is initiated bythe gradual addition of purified water to the powder blend, withcontinuous mixing, to change the consistency of the dry powderingredients to granules. The wet granulation is dried in a fluid bed at40-60° C. for humidity reduction. Next, the dry granules are milledusing a rotary mill with a 1575 μm screen at less than 1200 rpm for sizereduction. Then, glidant, lubricant and the other half of thedisintegrant, previously sieved through a 30-mesh screen, are added andmixed for about 5 minutes.

The extended release layer (layer B) composition is prepared as follows:alprazolam and the ER polymer are first individually screened in arotary mill with a 991 μm screen, and then mixed with the filler 1,filler 2, and the inorganic salt previously milled using a hammer millwith a 0020 screen, in a mixer granulator for up to 10 minutes to form ahomogenous powder blend. The granulation process was initiated by thegradual addition of purified water to the powder blend, with continuousmixing, to change the consistency of the dry powder ingredients togranules. The wet granulation is dried in a fluid bed at 40-60° C. forhumidity reduction. Next, the dry granules are milled using a rotarymill with a 1575 μm screen at less than 1200 rpm for size reduction.Then, the glidant, plasticizer and lubricant, previously sieved througha 30-mesh screen, are added and mixed for about 5 minutes.

The multi-layered tablets are manufactured as follows: the IR/RRcomposition is loaded into the first hopper (first filled position) ofthe tableting machine, the ER composition is loaded into the secondhopper (second filled position) of the tableting machine, and the hardgelatin capsules are placed into the internal dispenser. The die isfirst filled with 60-255 mg of IR/RR composition, and then the hardgelatin capsule is dispensed onto the first composition. After that thedie is filled with 60-350 mg of ER composition and finally all thecomponents are compressed to obtained the multi-layered tablets.

EXAMPLE 9

The following procedure is used to prepare a multi-layered tabletcomprising a gastro-resistant coated core that provides a delayed andextended release of levodopa, and an external IR or RRcarbidopa-containing layer and an external ER entacapone-containinglayer in stacked arrangement with respect to and on opposite sides ofthe gastro-resistant coated core. An exemplary formulation is disclosedbelow.

Ingredients/functional category Amount (mg) Gastro-resistant coated coreCore (ER) Levodopa 200.0 Filler 10.0-200.0 CR polymer 2.0-40.0 Glidant0.4-10   Lubricant 2.0-10.0 Enteric coating (DR) Enteric film polymer 5.0-200.0 Plasticizer (optional) 0.1-20.0 Plasticizer 0.3-1.5  DryCoating Layer A (IR/RR) Carbidopa  50.0 Filler 1 20.0-150.0 Filler 220.0-150.0 Binder 5.0-50.0 Disintegrant 5.0-20.0 Glidant 0.2-5.0 Lubricant 1.0-5.0  Layer B (ER) Entacapone 200.0 CR Polymer 1.0-15.0Filler 1 20.0-300.0 Filler 2 20.0-300.0 Plasticizer 10.0-50.0  Inorganicsalt 1.0-30.0 Glidant 0.2-5.0  Lubricant 1.0-5.0 

The ER core composition is prepared as follows: the levodopa and CRpolymer are first individually screened in a rotary mill with a 991 μmscreen, and then mixed with filler, in a mixer granulator for up to 10minutes to form a homogenous powder blend. The granulation process isinitiated by the gradual addition of purified water to the powder blend,with continuous mixing, to change the consistency of the dry powderingredients to granules. The wet granulation is dried in a static bed at50-70° C. or in a fluid bed at 40-60° C. for humidity reduction. Next,the dry granules are milled using a rotary mill with a 1575 μm screen atless than 1200 rpm for size reduction. Then, the glidant and thelubricant, previously sieved through a 30-mesh screen, are added andmixed for about 5 minutes. The final blend is tableted to provide thecores.

The enteric coating composition is prepared as follows: the enteric filmpolymer, and the plasticizer are blended in purified water to form apolymer suspension. This suspension is sprayed onto the cores in aperforated pan coater to obtain gastro-resistant coated cores.

The IR/RR composition (layer A) is prepared as follows: carbidopa,filler 1, filler 2, binder, and half of the disintegrant are firstindividually screened in a rotary mill with a 991 μm screen, and thenmixed in a mixer granulator for up to 10 minutes to form a homogenouspowder blend. The granulation process is initiated by the gradualaddition of purified water to the powder blend, with continuous mixing,to change the consistency of the dry powder ingredients to granules. Thewet granulation is dried in a static bed at 50-70° C. or in a fluid bedat 40-60° C. for humidity reduction. Next, the dry granules are milledusing a rotary mill with a 1575 μm screen at less than 1200 rpm for sizereduction. Then, the glidant, lubricant, and the other half of thedisintegrant, previously sieved through a 30-mesh screen, are added andmixed for about 5 minutes to obtain the IR/RR composition.

The ER layer (layer B) composition is prepared as follows: entacaponeand the CR polymer are first individually screened in a rotary mill witha 991 μm screen, and then mixed with filler 1, filler 2 and inorganicsalt previously milled using a hammer mill with a 0020 screen, in amixer granulator for up to 10 minutes to form a homogenous powder blend.The granulation process is initiated by the gradual addition of purifiedwater to the powder blend, with continuous mixing, to change theconsistency of the dry powder ingredients to granules. The wetgranulation is dried in a static bed at 50-70° C. or in a fluid bed at40-60° C. for humidity reduction. Next, the dry granules are milledusing a rotary mill with a 1575 μm screen at less than 1200 rpm for sizereduction. Then, the glidant, plasticizer, and lubricant, previouslysieved through a 30-mesh screen, are added and mixed for about 5 minutesto obtain the ER composition.

The multi-layered tablets are manufactured as follows: the IR/RRcomposition is loaded into the first hopper (first filled position) ofthe tableting machine, the ER composition is loaded into the secondhopper (second filled position) of the tableting machine, and the drygastro-resistant coated cores are placed into the internal coredispenser. The die is first filled with 100-430 mg of IR/RR composition,and then the gastro-resistant coated core is dispensed onto the firstcomposition. After that the die is filled with 250-900 mg of ERcomposition and finally all the components are compressed to obtainedthe multi-layered tablets.

EXAMPLE 10

The following procedure is used to prepare a multi-layered tabletcomprising a gastro-resistant coated core that provides a delayed andextended release of levodopa, and an external IR or RRlevodopa/carbidopa-containing layer and an external ERentacapone-containing layer in stacked arrangement with respect to andon opposite sides of the gastro-resistant coated core. An exemplaryformulation is disclosed below.

Ingredients/functional category Amount (mg) Gastro-resistant coated coreCore (ER) Levodopa 100.0 Filler  5.0-100.0 CR polymer 1.0-20.0 Glidant0.2-5.0  Lubricant 1.0-5.0  Enteric coating (DR) Enteric film polymer 5.0-200.0 Plasticizer (optional) 0.1-20.0 Plasticizer 0.3-1.5  DryCoating Layer A (IR/RR) Levodopa 100.0 Carbidopa  50.0 Filler 120.0-300.0 Filler 2 20.0-300.0 Binder 5.0-50.0 Disintegrant 5.0-20.0Glidant 0.2-5.0  Lubricant 1.0-5.0  Layer B (ER) Entacapone 200.0 CRPolymer 1.0-15.0 Filler 1 20.0-300.0 Filler 2 20.0-300.0 Plasticizer10.0-50.0  Inorganic salt 1.0-30.0 Glidant 0.2-5.0  Lubricant 1.0-5.0 

The ER core composition is prepared as follows: the levodopa and CRpolymer are first individually screened in a rotary mill with a 991 μmscreen, and then mixed with filler, in a mixer granulator for up to 10minutes to form a homogenous powder blend. The granulation process isinitiated by the gradual addition of purified water to the powder blend,with continuous mixing, to change the consistency of the dry powderingredients to granules. The wet granulation is dried in a static bed at50-70° C. or in a fluid bed at 40-60° C. for humidity reduction. Next,the dry granules are milled using a rotary mill with a 1575 μm screen atless than 1200 rpm for size reduction. Then, the glidant and thelubricant, previously sieved through a 30-mesh screen, are added andmixed for about 5 minutes. The final blend is tableted to provide thecores.

The enteric coating composition is prepared as follows: the enteric filmpolymer, and the plasticizer are blended in purified water to form apolymer suspension. This suspension is sprayed onto the cores in aperforated pan coater to obtain gastro-resistant coated cores.

The IR/RR composition (layer A) is prepared as follows: the levodopa,carbidopa, filler 1, filler 2, binder, and half of the disintegrant arefirst individually screened in a rotary mill with a 991 μm screen, andthen mixed in a mixer granulator for up to 10 minutes to form ahomogenous powder blend. The granulation process is initiated by thegradual addition of purified water to the powder blend, with continuousmixing, to change the consistency of the dry powder ingredients togranules. The wet granulation is dried in a static bed at 50-70° C. orin a fluid bed at 40-60° C. for humidity reduction. Next, the drygranules are milled using a rotary mill with a 1575 μm screen at lessthan 1200 rpm for size reduction. Then, the glidant, lubricant, and theother half of the disintegrant, previously sieved through a 30-meshscreen, are added and mixed for about 5 minutes to obtain the IR/RRcomposition.

The ER layer (layer B) composition is prepared as follows: entacaponeand the CR polymer are first individually screened in a rotary mill witha 991 μm screen, and then mixed with filler 1, filler 2 and inorganicsalt previously milled using a hammer mill with a 0020 screen, in amixer granulator for up to 10 minutes to form a homogenous powder blend.The granulation process is initiated by the gradual addition of purifiedwater to the powder blend, with continuous mixing, to change theconsistency of the dry powder ingredients to granules. The wetgranulation is dried in a static bed at 50-70° C. or in a fluid bed at40-60° C. for humidity reduction. Next, the dry granules are milledusing a rotary mill with a 1575 μm screen at less than 1200 rpm for sizereduction. Then, the glidant, plasticizer, and lubricant, previouslysieved through a 30-mesh screen, are added and mixed for about 5 minutesto obtain the ER composition.

The multi-layered tablets are manufactured as follows: the IR/RRcomposition is loaded into the first hopper (first filled position) ofthe tableting machine, the ER composition is loaded into the secondhopper (second filled position) of the tableting machine, and the drygastro-resistant coated cores are placed into the internal coredispenser. The die is first filled with 200-830 mg of IR/RR composition,and then the gastro-resistant coated core is dispensed onto the firstcomposition. After that the die is filled with 250-900 mg of ERcomposition and finally all the components are compressed to obtainedthe multi-layered tablets.

EXAMPLE 11

The following procedure is used to prepare a multi-layered tabletcomprising an osmotic device (intermediate drug-containing composition)that provides domperidone ER, and an external IR or RRergotamine-containing layer and an external ER naproxen-containing layerin stacked arrangement with respect to and on opposite sides of theosmotic core. An exemplary formulation is disclosed below.

Ingredients/functional category Amount (mg) Osmotic device CoreDomperidone 10  Filler 1 50.0-200.0 Binder 5.0-20.0 Glidant 0.15-3.0 Lubricant 0.5-5.0  Osmotic agent 0-70 Filler 2 50.0-150.0 SemipermeableMembrane Cellulose ester 1   0-20.0 Cellulose ester 2   0-20.0Plasticizer 0.3-1.5  Dry Coating Layer A (IR/RR) Ergotamine  1.0 Filler1 50.0-350.0 Filler 2 50.0-200.0 Binder 5.0-30.0 Disintegrant 5.0-25.0Glidant 0.2-5.0  Lubricant 1.0-5.0  Layer B (ER) Naproxen 500.0 ERPolymer  1.0-150.0 Filler 1 50.0-350.0 Filler 2 50.0-200.0 Inorganicsalt 1.0-30.0 Glidant 0.2-5.0  Lubricant 1.0-5.0 

Domperidone, filler 1, filler 2, and a binder, are first individuallyscreened to a uniform size using a Quadro Comil at less than 500 rpm,and then mixed with osmotic agent previously milled using a Fitz Millwith a screen 0020-0069 at less than 8000 rpm, in a mixer granulator forup to 5 minutes to form a homogenous powder blend. The granulationprocess is initiated by the gradual addition of purified water to thepowder blend, with continuous mixing, to change the consistency of thedry powder ingredients to granules. The wet granulation is sievedthrough a Quadro Comil at a speed less than 500 rpm, and then dried in astatic bed at 50° C. for humidity reduction. Next, the dry granules aremilled using a Quadro Comil with a screen R991μ at less than 2,000 rpmfor size reduction. Then, a mixture of a glidant and a lubricant,previously sieved through a 60-mesh screen, is added and mixed for about5 minutes. The resulting mixture is compressed in a compressor with 6-10mm diameter punches to form uncoated cores.

A semipermeable membrane composition is prepared as follows: celluloseester 1, cellulose ester 2, and a plasticizer of low molecular weightare blended in acetone and purified water. The blend is sprayed onto theuncoated cores to obtain coated cores. The semipermeable membrane weightrange is approximately between 10 and 40 mg. The coated cores are thenperforated with a laser equipment to form at least one passageway of0.2-0.8 mm of diameter.

The IR/RR composition (layer A) is prepared as follows: the ergotamine,filler 1, filler 2, binder and half of the disintegrant are firstindividually screened in a rotary mill with a 991 μm screen, and thenmixed in a mixer granulator for up to 10 minutes to form a homogenouspowder blend. The granulation process is initiated by the gradualaddition of purified water to the powder blend, with continuous mixing,to change the consistency of the dry powder ingredients to granules. Thewet granulation is dried in a static bed at 50-70° C. or in a fluid bedat 40-60° C. for humidity reduction. Next, the dry granules are milledusing a rotary mill with a 1575 μm screen at less than 1200 rpm for sizereduction. Then, glidant, lubricant, and the other half of thedisintegrant, previously sieved through a 30-mesh screen, are added andmixed for about 5 minutes to obtain the IR/RR composition.

The ER layer (layer B) composition is prepared as follows: the naproxenand ER polymer are first individually screened in a rotary mill with a991 μm screen, and then mixed with filler 1, filler 2 and inorganic saltpreviously milled using a hammer mill with a 0020 screen, in a mixergranulator for up to 10 minutes to form a homogenous powder blend. Thegranulation process is initiated by the gradual addition of purifiedwater to the powder blend, with continuous mixing, to change theconsistency of the dry powder ingredients to granules. The wetgranulation is dried in a static bed at 50-70° C. or in a fluid bed at40-60° C. for humidity reduction. Next, the dry granules are milledusing a rotary mill with a 1575 μm screen at less than 1200 rpm for sizereduction. Then, the glidant and lubricant, previously sieved through a60-mesh screen, are added and mixed for about 5 minutes to obtain the ERlayer composition.

The multi-layered tablets are manufactured as follows: the IR/RRcomposition is loaded into the first hopper (first filled position) ofthe tableting machine, the ER composition is loaded into the secondhopper (second filled position) of the tableting machine, and theosmotic cores are placed into the internal core dispenser. The die isfirst filled with 150-550 mg of IR/RR composition, and then the osmoticcore is dispensed onto the first composition. After that the die isfilled with 150-900 mg of ER composition and finally all the componentsare compressed to obtained the multi-layered tablets.

The above is a detailed description of particular embodiments of theinvention. It is recognized that departures from the disclosedembodiments may be made within the scope of the invention and thatobvious modifications will occur to a person skilled in the art. Thoseof skill in the art should, in light of the present disclosure,appreciate that many changes can be made in the specific embodimentswhich are disclosed herein and still obtain a like or similar resultwithout departing from the spirit and scope of the invention. All of theembodiments disclosed and claimed herein can be made and executedwithout undue experimentation in light of the present disclosure.

1. A combination release tablet comprising: a) a drug-containing rapidrelease first compressed composition comprising at least one drug; b) adrug-containing extended release second compressed compositioncomprising at least one drug and a release rate modifier; and c) apreformed and film-coated extended release intermediate drug-containingcomposition comprising a drug-containing core surrounded by a coating;wherein the first compressed composition and second compressedcomposition oppose one another, are in direct contact with, in stackedarrangement with respect to, and disposed on opposite faces or surfacesof the intermediate drug-containing composition, whereby the tabletprovides three different active agent release profiles.
 2. The tablet ofclaim 1, wherein the preformed and film-coated extended releaseintermediate drug-containing composition is an osmotic device comprisinga core surrounded by a membrane having a preformed passageway throughit.
 3. The tablet of claim 2, wherein the membrane is a semipermeablemembrane, a microporous membrane, or an impermeable membrane.
 4. Thetablet of claim 3, wherein (i) the preformed passageway is not plugged,or (ii) the preformed passageway is plugged by the first or secondcompressed composition and initial release of drug from the core isdelayed.
 5. (canceled)
 6. The tablet of claim 1, wherein the preformedand film-coated extended release intermediate drug-containingcomposition is a capsule comprising a shell enclosing a drug-containingcomposition.
 7. The tablet of claim 6, wherein the shell comprises atleast one preformed passageway.
 8. The tablet of claim 7, wherein theshell is erodible, swellable, degradable and/or soluble in aqueousmedium.
 9. The tablet of claim 6, wherein the shell is erodible,swellable, degradable and/or soluble in aqueous medium and thedrug-containing composition further comprises a release rate modifier.10. The tablet of claim 6, wherein the shell is a releaserate-controlling shell.
 11. The tablet of claim 6, wherein the shell isnot a release rate controlling shell and the drug-containing compositionwithin the shell comprises a release rate-controlling material.
 12. Thetablet of claim 1, wherein the preformed and film-coated extendedrelease intermediate drug-containing composition is a gastro-resistantcoated core comprising a gastro-resistant coating surrounding adrug-containing composition.
 13. The tablet of claim 12, wherein thecore comprises a release rate-controlling material.
 14. The tablet ofclaim 13, wherein the gastro-resistant coated core is adapted forrelease of drug downstream of the gastric region following oraladministration of the tablet to a subject.
 15. The tablet of claim 14,wherein (i) the gastro-resistant coated core is adapted for release ofdrug in the intestine following oral administration of the tablet to asubject, or (ii) the gastro-resistant coated core is adapted for releaseof drug in the colon following oral administration of the tablet to asubject.
 16. (canceled)
 17. The tablet of claim 1, wherein the tabletcomprises three different drugs.
 18. The tablet of claim 17, wherein adrug in the first compressed composition is different than a drug in thesecond compressed composition.
 19. The tablet of claim 18, wherein (i) adrug in the first compressed composition is different than a drug in thedrug-containing core, or (ii) the drug in the second compressedcomposition is different than the drug in the drug-containing core. 20.(canceled)
 21. The tablet of claim 17, wherein (i) the drug in the firstcompressed composition is the same as the drug in the drug-containingcore, (ii) the first compressed composition comprises two differentdrugs, the core comprises the third different drug, and the secondcompressed composition comprises a charge of either one of the threedifferent drugs, or (iii) the first compressed composition comprises acharge of each of two different drugs, the core comprises a charge ofthe third different drug, and the second compressed compositioncomprises an additional charge of either one of the three differentdrugs.
 22. (canceled)
 23. (canceled)
 24. The tablet of claim 17, whereinthe drug in the first compressed composition is the same as the drug inthe second compressed composition.
 25. The tablet of claim 24, wherein(i) the drug in the first compressed composition is the same as the drugin the drug-containing core, or (ii) the drug in the second compressedcomposition is different than the drug in the drug-containing core. 26.(canceled)
 27. The tablet according to anyone of claims 2-4, wherein (i)the rapid release first compressed composition comprises carbidopa andoptionally levodopa; the extended release second compressed compositioncomprises levodopa; and the intermediate drug-containing compositioncomprises amantadine. (ii) the rapid release first compressedcomposition comprises ondensetron; the extended release secondcompressed composition comprises alprazolam; and the intermediatedrug-containing composition comprises venlafaxine, (iii) the rapidrelease first compressed composition comprises carbidopa and optionallylevodopa; the extended release second compressed composition compriseslevodopa; and the intermediate drug-containing composition comprisesropinirole, (iv) the rapid release first compressed compositioncomprises ondensetron; the extended release second compressedcomposition comprises quetiapene; and the intermediate drug-containingcomposition comprises venlafaxine, (v) the rapid release firstcompressed composition comprises quetiapene; the extended release secondcompressed composition comprises divalproex sodium; and the intermediatedrug-containing composition comprises lithium, or (vi) the rapid releasefirst compressed composition comprises ergotamine; the extended releasesecond compressed composition comprises naproxen; and the intermediatedrug-containing composition comprises domperidone.
 28. (canceled) 29.(canceled)
 30. (canceled)
 31. (canceled)
 32. The tablet according toanyone of claims 6-11, wherein the rapid release first compressedcomposition comprises ondensetron; the extended release secondcompressed composition comprises alprazolam; and the intermediatedrug-containing composition comprises venlafaxine.
 33. The tablet ofclaims 12 or 13, wherein (i) the rapid release first compressedcomposition comprises carbidopa and optionally levodopa; the extendedrelease second compressed composition comprises amantadine; and theintermediate drug-containing composition comprises levodopa, or (ii) therapid release first compressed composition comprises carbidopa andoptionally levodopa; the extended release second compressed compositioncomprises entacapone; and the intermediate drug-containing compositioncomprises levodopa.
 34. (canceled)
 35. (canceled)